Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme

ABSTRACT

Disclosed are chemical entities that inhibit ubiquitin-activating enzyme (UAE), each of which is a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein Y is 
     
       
         
         
             
             
         
       
     
     and W, Z, X Y , R Y1 , R Y2  and R Y3  are defined herein; pharmaceutical compositions comprising the chemical entities; and methods of using the chemical entities. These chemical entities are useful for treating disorders, particularly cell proliferation disorders, including cancers.

This application claims priority from U.S. Provisional PatentApplication Ser. No. 61/600,070, filed on Feb. 17, 2012, which is herebyincorporated by reference in its entirety.

BACKGROUND

Ubiquitin is a small 76-amino acid protein that is the founding memberof a family of posttranslational modifiers known as the ubiquitin-likeproteins (UbIs). UbIs play key roles in controlling many biologicalprocesses including cell division, cell signaling and the immuneresponse. UbIs are small proteins that are covalently attached to alysine on a target protein via an isopeptide linkage with a C-terminalglycine of the ubI. The UbI molecule alters the molecular surface of thetarget protein and can affect such properties as protein-proteininteractions, enzymatic activity, stability and cellular localization ofthe target.

There are 8 known human UbI activating enzymes (known as E1s) (Schulman,B. A., and J. W. Harper, 2009, Ubiquitin-like protein activation by E1enzymes: the apex for downstream signalling pathways, Nat Rev Mol CellBiol 10:319-331). Ubiquitin and other ubIs are activated by a specificE1 enzyme which catalyzes the formation of an acyl-adenylateintermediate with the C-terminal glycine of the ubI. The activated ubImolecule is then transferred to the catalytic cysteine residue withinthe E1 enzyme through formation of a thioester bond intermediate. TheE1-ubI intermediate and an E2 interact, resulting in a thioesterexchange wherein the ubI is transferred to the active site cysteine ofthe E2. The ubI is then conjugated to the target protein, eitherdirectly or in conjunction with an E3 ligase, through isopeptide bondformation with the amino group of a lysine side chain in the targetprotein. Eukaryotic cells possess ˜35 ubiquitin E2 enzymes and >500ubiquitin E3 enzymes. The E3 enzymes are the specificity factors of theubiquitin pathway which mediate the selective targeting of specificcellular substrate proteins (Deshaies, R. J., and C. A. Joazeiro, 2009,RING domain E3 ubiquitin ligases, Annu Rev Biochem 78:399-434;Lipkowitz, S., and A. M. Weissman, 2011, RINGs of good and evil: RINGfinger ubiquitin ligases at the crossroads of tumour suppression andoncogenesis, Nat Rev Cancer 11:629-643; Rotin, D., and S. Kumar, 2009,Physiological functions of the HECT family of ubiquitin ligases, Nat RevMol Cell Biol 10:398-409).

Two E1 enzymes have been identified for ubiquitin, UAE(ubiquitin-activating enzyme) and UBA6 (Jin, J., et al., 2007, Dual E1activation systems for ubiquitin differentially regulate E2 enzymecharging, Nature 447:1135-1138). UAE is the E1 responsible for themajority of ubiquitin flux within the cell. UAE is capable of chargingeach of the approximately ˜35 E2 enzymes with the exception of Usel,which is the only E2 known to exclusively work with UBA6 (Jin et al.,2007). Inhibition of UAE is sufficient to dramatically impair the greatmajority of ubiquitin-dependent cellular processes (Ciechanover, A., etal., 1984, Ubiquitin dependence of selective protein degradationdemonstrated in the mammalian cell cycle mutant ts85, Cell 37:57-66;Finley, D., A. et al., 1984, Thermolability of ubiquitin-activatingenzyme from the mammalian cell cycle mutant ts85, Cell 37:43-55).

The cellular signals generated by ubiquitin are diverse. Ubiquitin canbe attached to substrates as a single entity or as polyubiquitinpolymers generated through isopeptide linkages between the C-terminus ofone ubiquitin and one of the many lysines on a second ubiquitin. Thesevaried modifications are translated into a variety of cellular signals.For example, conjugation of a lysine 48-linked polyubiquitin chain to asubstrate protein is predominantly associated with targeting the proteinfor removal by the 26S proteasome. A single ubiquitin modification, ormonoubiquination, typically affects protein localization and/orfunction. For example, monoubiquitination modulates the function ofHistones 2a and 2b (Chandrasekharan, M. B., et al., 2010, Histone H2Bubiquitination and beyond: Regulation of nucleosome stability, chromatindynamics and the trans-histone H3 methylation, Epigenetics 5:460-468),controls the nucleocytoplasmic shuttling of PTEN (Trotman, L. C., etal., 2007, Ubiquitination regulates PTEN nuclear import and tumorsuppression, Cell 128:141-156), drives localization of the FANCD2protein to sites of DNA damage (Gregory, R. C., et al., 2003, Regulationof the Fanconi anemia pathway by monoubiquitination, Semin Cancer Biol13:77-82) and promotes the internalization and endosomal/lysosomalturnover of some cell surface receptors like EGFR (Mosesson, Y., and Y.Yarden, 2006, Monoubiquitylation: a recurrent theme in membrane proteintransport. Isr Med Assoc J 8:233-237). Other forms of polyubiquitinationinclude lysine 11, 29 and 63 chains which play various roles in the cellincluding the cell cycle, DNA repair and autophagy (Behrends, C., and J.W. Harper, 2011, Constructing and decoding unconventional ubiquitinchains, Nat Struct Mol Biol 18:520-528; Bennett, E. J., and J. W.Harper, 2008, DNA damage: ubiquitin marks the spot, Nat Struct Mol Biol15:20-22; Komander, D., 2009, The emerging complexity of proteinubiquitination, Biochem Soc Trans 37:937-953).

UAE-initiated ubiquitin conjugation plays an important role in proteinhomeostasis, cell surface receptor trafficking, transcription factorturnover and cell cycle progression. Many of these processes areimportant for cancer cell survival and it is believed that tumor cellsmay have increased sensitivity to UAE inhibition as a result of theirrapid growth rate, increased metabolic demands and oncogene fueledprotein stress. Disruption of protein homeostasis is a validatedtherapeutic approach for the treatment of cancer. VELCADE®(bortezomib),disrupts cellular protein homeostasis and is approved for the treatmentof multiple myeloma and mantle cell lymphoma. MLN4924, an E1 inhibitorof the Nedd8-activating enzyme (NAE) is currently in clinical oncologytrials (Soucy, T. A., et al., 2009, An inhibitor of NEDD8-activatingenzyme as a new approach to treat cancer, Nature 458:732-736; Soucy, T.A., et al., 2009, Targeting NEDD8-activated cullin-RING ligases for thetreatment of cancer, Clin Cancer Res 15:3912-3916) and numerous othertargets within the ubiquitin/protein homeostasis arena are of interestfor oncology (Nalepa, G., et al., 2006, Drug discovery in theubiquitin-proteasome system, Nat Rev Drug Discov 5:596-613). Preclinicalstudies with PYZD-4409, a UAE inhibitor, showed that it induced celldeath in both leukemia and myeloma cell lines and demonstratedanti-tumor activity in a mouse acute myeloid leukemia (AML model). (Xu,W. G., et al., 2010, The ubiquitin-activating enzyme E1 as a therapeutictarget for the treatment of leukemia and multiple myeloma, Blood,115:2251-59). Thus, UAE represents a novel protein homeostasis targetopportunity for the treatment of cancer.

It is believed that UAE inhibitors would also be applicable for thetreatment of other diseases and conditions outside of oncology due tothe vast role of ubiquitin in cellular process; for example, proteasomeinhibitors, which like UAE inhibitors alter cellular proteinhomeostasis, show promise for the treatment of antibody mediatedtransplant rejection (Woodle, E. S., et al., 2011, Proteasome inhibitortreatment of antibody-mediated allograft rejection, Curr Opin OrganTransplant 16:434-438), ischemic brain injury, infection, and autoimmunedisorders (Kisselev, A. F., et al., 2012, Proteasome inhibitors: anexpanding army attacking a unique target, Chem Biol 19:99-115).Ubiquitin-dependent signaling and degradation are important for theactivation of pro-inflammatory pathways such as the NF-kB pathwayimplicating UAE inhibitors as potential anti-inflammatory agents Wertz,I. E., and Dixit, V. M., 2010, Signaling to NF-kappaB: regulation byubiquitination, Cold Spring Harb Perspect Biol, 2:a003350).

SUMMARY

In one aspect, the invention relates to chemical entities, each of whichis a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein W, Y and Z aredefined as below.

In one aspect, the invention relates to compositions comprising one ormore of the chemical entities and one or more pharmaceuticallyacceptable carriers.

In one aspect, the invention relates to methods of treating cancercomprising administering to a patient in need of such treatment one ormore of the chemical entities.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an x-ray powder diffraction (XRPD) pattern for crystallineForm 1 anhydrous(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 2 shows a differential scanning calorimetry (DSC) thermogram forcrystalline Form 1 anhydrous(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 3 shows a thermogravimetric analysis (TGA) thermogram forcrystalline Form 1 anhydrous(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 4 shows a raman pattern for crystalline Form 1 anhydrous(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 5A shows a raman pattern in the region of 1450 cm⁻¹ to 1520 cm⁻¹for crystalline Form 1 anhydrous(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 5B shows a raman pattern in the region of 1450 cm⁻¹ to 1520 cm⁻¹for crystalline Form 2 monohydrated(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 6A shows a raman pattern in the region of 1100 cm⁻¹ to 1240 cm⁻¹for crystalline Form 1 anhydrous(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 6B shows a raman pattern in the region of 1100 cm⁻¹ to 1240 cm⁻¹for crystalline Form 2 monohydrated(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 7A shows a raman pattern in the region of about 700 cm⁻¹ to about1100 cm⁻¹ for crystalline Form 1 anhydrous(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 7B shows a raman pattern in the region of about 700 cm⁻¹ to about1100 cm⁻¹ for crystalline Form 2 monohydrated(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 8 shows an x-ray powder diffraction (XRPD) pattern for crystallineForm 2 monohydrated(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 9 shows a differential scanning calorimetry (DSC) thermogram forcrystalline Form 2 monohydrated(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 10 shows a thermogravimetric analysis (TGA) thermogram forcrystalline Form 2 monohydrated(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate.

FIG. 11 shows a raman pattern for crystalline Form 2 monohydrated(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate.

DESCRIPTION Definitions

Unless otherwise specified, as used herein, alone or as part of anothergroup, “halo” or “halogen” refers to fluoro, chloro, bromo or iodo.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “alkyl” refers to a straight-chain or branched saturatedhydrocarbyl group having from 1 to 8 carbon atoms. In some embodiments,an alkyl group can have from 1 to 6 carbon atoms. In some embodiments,an alkyl group can have from 1 to 4 carbon atoms. In some embodiments,an alkyl group can have from 1 to 3 carbon atoms. Examples of C₁₋₃ alkylgroups include methyl, ethyl, propyl and isopropyl. Examples of C₁₋₄alkyl groups include the aforementioned C₁₋₃ alkyl groups as well asbutyl, isobutyl, sec-butyl and tert-butyl. Examples of C₁₋₆ alkyl groupsinclude the aforementioned C₁₋₄ alkyl groups as well as pentyl,isopentyl, neopentyl, hexyl and the like. Additional examples of alkylgroups include heptyl, octyl and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “alkenyl” refers to a straight-chain or branched hydrocarbylgroup having from 2 to 8 carbon atoms and one or more carbon-carbondouble bonds. In some embodiments, an alkenyl group can have from 2 to 6carbon atoms. In some embodiments, an alkenyl group can have from 2 to 4carbon atoms. The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, butadienyl and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkenyl groups as well as pentenyl,pentadienyl, hexenyl and the like. Additional examples of alkenylinclude heptenyl, octenyl, octatrienyl and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “alkynyl” refers to a straight-chain or branched hydrocarbylgroup having from 2 to 8 carbon atoms and one or more carbon-carbontriple bonds. In some embodiments, an alkynyl group can have from 2 to 6carbon atoms. In some embodiments, an alkynyl group can have from 2 to 4carbon atoms. The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include ethynyl, propyn-1-yl, propyn-3-yl,1-butyn-1-yl, 1-butyn-4-yl, 2-butyn-1-yl and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkynyl groups as well aspentynyl, hexynyl and the like. Additional examples of alkynyl includeheptynyl, octynyl and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “aliphatic” refers to alkyl, alkenyl and alkynyl groups asdefined above. For example, if a moiety can be substituted with “C₁₋₆aliphatic”, it can be substituted with C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl.

Unless otherwise specified, each instance of “optionally substituted”alkyl, alkenyl or alkynyl (collectively, “optionally substituted”aliphatic) is independently unsubstituted or substituted with 1-3, 1-2or 1 substituent(s):

wherein

represents the alkyl, alkenyl or alkynyl group, respectively,

-   -   and each of m1, m2 and m3 is independently 0 (i.e., R^(S[1,2,3])        is —H) or 1.    -   In some embodiments, m1+m2+m3≦2. In some embodiments,        m1+m2+m3≦1.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “alkylene” refers to a diradical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 6 carbon atoms. In someembodiments, an alkylene group can have from 1 to 4 carbon atoms. Insome embodiments, an alkylene group can have from 1 to 2 carbon atoms.Examples of C₁₋₂ alkylene groups include methylene and ethylene.Examples of C₁₋₄ alkylene groups include the aforementioned C₁₋₂alkylene groups as well as trimethylene (1,3-propanediyl), propylene(1,2-propanediyl), tetramethylene (1,4-butanediyl), butylene(1,2-butanediyl), 1,3-butanediyl, 2-methyl-1,3-propanediyl and the like.Examples of C₁₋₆ alkylene groups include the aforementioned C₁₋₄alkylene groups as well as pentamethylene (1,5-pentanediyl), pentylene(1,2-pentanediyl), hexamethylene (1,6-hexanediyl), hexylene(1,2-hexanediyl), 2,3-dimethyl-1,4-butanediyl and the like. In someembodiments (“α,ω-alkylene”), an alkylene group is an α,ω-diradical.Examples of α,ω-alkylene groups include methylene, ethylene,trimethylene, tetramethylene, pentamethylene and hexamethylene.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “alkenylene” refers to a diradical of a straight-chain orbranched hydrocarbon group having from 2 to 6 carbon atoms and one ormore carbon-carbon double bonds. In some embodiments, an alkenylenegroup can have from 2 to 4 carbon atoms. In some embodiments, analkenylene group can have 2 carbon atoms, i.e., ethenediyl. The one ormore carbon-carbon double bonds can be internal (such as in1,4-but-2-enediyl) or terminal (such as in 1,4-but-1-enediyl). Examplesof C₂₋₄ alkenylene groups include ethenediyl, 1,2-propenediyl,1,3-propenediyl, 1,4-but-1-enediyl, 1,4-but-2-enediyl and the like.Examples of C₂₋₆ alkenylene groups include the aforementioned C₂₋₄alkenylene groups as well as 1,5-pent-1-enediyl, 1,4-pent-2-enediyl,1,6-hex-2-enediyl, 2,5-hex-3-enediyl, 2-methyl-1,4-pent-2-enediyl andthe like. In some embodiments (“α,ω-alkenylene”), an alkenylene group isan α,ω-diradical. Examples of α,ω-alkenylene groups include ethenediyl,1,3-propenediyl, 1,4-but-2-enediyl, 1,5-pent-1-enediyl,1,6-hex-3-enediyl and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “alkynylene” refers to a diradical of a straight-chain orbranched hydrocarbon group having from 2 to 6 carbon atoms and one ormore carbon-carbon triple bonds. In some embodiments, an alkynylenegroup can have from 2 to 4 carbon atoms. In some embodiments, analkynylene group can have 2 carbon atoms, i.e., ethynediyl. The one ormore carbon-carbon triple bonds can be internal (such as in1,4-but-2-ynediyl) or terminal (such as in 1,4-but-1-ynediyl). Examplesof C₂₋₄ alkynylene groups include ethynediyl, 1,3-propynediyl,1,4-but-1-ynediyl, 1,4-but-2-ynediyl and the like. Examples of C₂₋₆alkynylene groups include the aforementioned C₂₋₄ alkynylene groups aswell as 1,5-pent-1-ynediyl, 1,4-pent-2-ynediyl, 1,6-hex-2-ynediyl,2,5-hex-3-ynediyl, 3-methyl-1,5-hex-1-ynediyl and the like. In someembodiments (“α,ω-alkynylene”), an alkynylene group is an α,ω-diradical.Examples of α,ω-alkynylene groups include ethynediyl, 1,3-propynediyl,1,4-but-2-ynediyl, 1,5-pent-1-ynediyl, 1,6-hex-3-ynediyl and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “heteroalkylene” refers to a diradical having the structureC_(n1) alkylene[ψ]C_(n2) alkylene, wherein n1 and n2 are whole numbers,at least one of which is other than zero (C₀ alkylene is a covalentbond), and p is —O—, —NH—, —N(CH₃)— or —S—. C_(0-3,0-3) heteroalkylenerefers to C_(n1) alkylene[ψ]C_(n2) alkylene, wherein each of n1 and n2is independently 0, 1, 2 or 3, provided that n1+n2 is 1, 2, 3 or 4.C_(0-2,0-2) heteroalkylene refers to C_(n), alkylene[ψ]C_(n2) alkylene,wherein each of n1 and n2 is independently 0, 1 or 2, provided thatn1+n2 is 1, 2, 3 or 4. Examples of heteroalkylene groups include —OCH₂—,—NHCH₂CH₂—, SCH₂CH₂CH₂, —OCH(CH₃)CH₂—, —CH₂N(CH₃)—, —CH₂OCH₂—,—CH₂NHCH₂CH₂—, —CH₂SCH₂CH₂CH₂—, CH₂OCH(CH₃)CH₂—, —CH₂CH₂NH—,—CH₂CH₂N(CH₃)CH₂—, —CH₂CH₂OCH₂CH₂—, —CH(CH₃)CH₂S—, CH(CH₃)CH₂OCH₂— andthe like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “haloalkyl” refers to an alkyl group, wherein one or more of thehydrogen atoms are each independently replaced with halo. In someembodiments (“perhaloalkyl”), all of the hydrogen atoms are eachreplaced with fluoro or chloro. In some embodiments (“perfluoroalkyl”),all of the hydrogen atoms are each replaced with fluoro. Examples ofperfluoroalkyl groups include —CF₃, —CF₂CF₃, —CF₂CF₂CF₃ and the like.Examples of perhaloalkyl groups include the aforementionedperfluoroalkyl groups as well as —CCl₃, —CFCl₂, —CF₂Cl, —CCl₂CCl₃ andthe like. Examples of haloalkyl groups include the aforementionedperhaloalkyl groups as well as —CH₂F, —CHF₂, —CH₂Cl, —CH₂Br,—CH(Cl)CH₂Br, —CH₂CH(F)CH₂Cl and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “alkoxy” or “alkyloxy” refers to an —O-alkyl group having from 1to 8 carbon atoms. In some embodiments, an alkoxy group can have from 1to 6 carbon atoms. In some embodiments, an alkoxy group can have from 1to 4 carbon atoms. Examples of C₁₋₄ alkoxy groups include methoxy,ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like. Examplesof C₁₋₆ alkoxy groups include the aforementioned C₁₋₄ alkoxy groups aswell as pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.Additional examples of alkoxy groups include heptyloxy, octyloxy and thelike.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “haloalkoxy” refers to an alkoxy group, wherein one or more ofthe hydrogen atoms are each independently replaced with halo. In someembodiments (“perhaloalkoxy”), all of the hydrogen atoms are eachreplaced with fluoro or chloro. In some embodiments (“perfluoroalkoxy”),all of the hydrogen atoms are each replaced with fluoro. Examples ofperfluoroalkoxy groups include —OCF₃, —OCF₂CF₃, —OCF₂CF₂CF₃ and thelike. Examples of perhaloalkoxy groups include the aforementionedperfluoroalkoxy groups as well as —OCCl₃, —OCFCl₂, —OCF₂Cl, —OCCl₂CCl₃and the like. Examples of haloalkoxy groups include the aforementionedperhaloalkoxy groups as well as —OCH₂F, —OCHF₂, —OCH₂Cl, —OCH₂Br,—OCH(Cl)CH₂Br, —OCH₂CH(F)CH₂Cl and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “alkylthio” refers to an —S-alkyl group having from 1 to 8 carbonatoms. In some embodiments, an alkylthio group can have from 1 to 6carbon atoms. In some embodiments, an alkylthio group can have from 1 to4 carbon atoms. Examples of C₁₋₄ alkylthio groups include methylthio,ethylthio, propylthio, isopropylthio, butylthio, isobutylthio and thelike. Examples of C₁₋₆ alkylthio groups include the aforementioned C₁₋₄alkylthio groups as well as pentylthio, isopentylthio, hexylthio and thelike. Additional examples of alkylthio groups include heptylthio,octylthio and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “haloalkylthio” refers to an alkylthio group, wherein one or moreof the hydrogen atoms are each independently replaced with halo. In someembodiments (“perhaloalkylthio”), all of the hydrogen atoms are eachreplaced with fluoro or chloro. In some embodiments(“perfluoroalkylthio”), all of the hydrogen atoms are each replaced withfluoro. Examples of perfluoroalkylthio groups include —SCF₃, —SCF₂CF₃,—SCF₂CF₂CF₃ and the like. Examples of perhaloalkylthio groups includethe aforementioned perfluoroalkylthio groups as well as —SCCl₃, —SCFCl₂,—SCF₂Cl, —SCCl₂CCl₃ and the like. Examples of haloalkylthio groupsinclude the aforementioned perhaloalkylthio groups as well as —SCH₂F,—SCHF₂, —SCH₂Cl, —SCH₂Br, —SCH(Cl)CH₂Br, —SCH₂CH(F)CH₂Cl and the like.

Illustrative examples of aryl, carbocyclyl, heteroaryl, heterocyclyl,fused aryl, fused carbocyclyl, fused heteroaryl and fused heterocyclylare shown in the table below, in which X represents a heteroatom such asN, O or S. These examples are intended merely to illustrate thedifferences between the radicals and are not in any way intended tolimit any other feature shown, e.g., position of attachment (except inthe fused rings, where the point of attachment must be on the ring typeshown), position of the heteroatom(s), number of heteroatoms, size ofrings, number of rings, etc.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “aryl” refers to a radical of an aromatic monocyclic or bicyclicring system having from 6 to 10 ring carbon atoms. Examples of such arylgroups include phenyl, 1-naphthyl and 2-naphthyl and the like.

Unless otherwise specified, each instance of an “optionally substituted”aryl group is independently unsubstituted or substituted with 1-4, 1-3,1-2 or 1 substituent(s):

wherein

represents the aryl group,

-   -   and each of m7, m7″, m8 and m9 is independently 0 (i.e.,        R^(S[7,8,9]) is —H) or 1.    -   In some embodiments, m7+m7″+m8+m9≦3. In some embodiments,        m7+m7″+m8+m9≦2. In some embodiments, m7+m7″+m8+m9≦1.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “carbocyclyl” refers to a radical of a non-aromatic cyclichydrocarbon group having from 3 to 10 ring carbon atoms. In someembodiments (“C₃₋₈ carbocyclyl”), a carbocyclyl group has from 3 to 8ring carbon atoms. In some embodiments (“C₃₋₆ carbocyclyl”), acarbocyclyl group has from 3 to 6 ring carbon atoms. Examples of C₃₋₆carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like.Examples of C₃₋₈ carbocyclyl groups include the aforementioned C₃₋₆carbocyclyl groups as well as cycloheptyl, cycloheptadienyl,cycloheptatrienyl, cyclooctyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl and the like. Examples of C₃₋₁₀ carbocyclyl groupsinclude the aforementioned C₃₋₈ carbocyclyl groups as well asoctahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and thelike. As the foregoing examples illustrate, a carbocyclyl group can bemonocyclic or bicyclic (e.g., containing a fused, bridged or spiro ringsystem), and can be saturated or can contain one or more carbon-carbondouble or triple bonds.

In some embodiments (“cycloalkyl”), a carbocyclyl group is monocyclic,saturated, and has 3 to 8 ring carbon atoms. In some embodiments (“C₃₋₆cycloalkyl”), a cycloalkyl group has 3 to 6 ring carbon atoms. In someembodiments (“C₅₋₆ cycloalkyl”), a cycloalkyl group has 5 or 6 ringcarbon atoms. Examples of C₅₋₆ cycloalkyl groups include cyclopentyl andcyclohexyl. Examples of C₃₋₆ cycloalkyl groups include theaforementioned C₅₋₆ cycloalkyl groups as well as cyclopropyl andcyclobutyl. Examples of C₃₋₈ cycloalkyl groups include theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl andcyclooctyl.

Unless otherwise specified, each instance of an “optionally substituted”carbocyclyl group is independently unsubstituted or substituted with1-3, 1-2 or 1 substituent(s):

wherein

represents the carbocyclyl group,

-   -   and each of m4, m5 and m6 is independently 0 (i.e., R^(S[4,5,6])        is —H) or 1.    -   In some embodiments, m4+m5+m6≦2. In some embodiments,        m4+m5+m6≦1.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “heteroaryl” refers to a radical of a 5- to 10-membered aromaticring system having ring carbon atoms and 1 to 4 ring heteroatoms, eachheteroatom independently selected from N, O and S. Examples of suchheteroaryl groups include pyrrolyl, furanyl (furyl), thiophenyl(thienyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (pyridyl),pyridazinyl, pyrimdinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl,benzothiophenyl (benzothienyl), indazolyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl and the like.

As the foregoing examples illustrate, a heteroaryl group can bemonocyclic or bicyclic. In some embodiments the heteroaryl group ismonocyclic and has 5 to 6 ring atoms. In some embodiments the heteroarylgroup is monocyclic and has 5 to 6 ring atoms, 1 or 2 of which areheteroatoms. In some embodiments the heteroaryl group is bicyclic andhas 8 to 10 ring atoms. In some embodiments the heteroaryl group isbicyclic and has 9 to 10 ring atoms, 1-3 of which are heteroatoms. Insome embodiments the heteroaryl group is bicyclic and has 9 to 10 ringatoms, 1 or 2 of which are heteroatoms.

Unless otherwise specified, each instance of an “optionally substituted”heteroaryl group is independently unsubstituted or substituted with 1-4,1-3, 1-2 or 1 substituent(s):

wherein

represents the heteroaryl group,

-   -   and each of m7, m7″, m8 and m9 is independently 0 (i.e.,        R^(S[7,8,9]) is —H) or 1.    -   In some embodiments, m7+m7″+m8+m9≦3. In some embodiments,        m7+m7″+m8+m9≦2. In some embodiments, m7+m7″+m8+m9≦1.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “heterocyclyl” refers to a radical of a monocyclic 3- to7-membered non-aromatic ring system having ring carbon atoms and 1 to 3ring heteroatoms, each heteroatom independently selected from N, O andS, wherein each ring carbon atom that is bonded to a ring heteroatom canalso be bonded to an oxo (═O) group (such that the ring carbon atom isthe carbon atom of a carbonyl (—C(═O)— group). Examples of heterocyclylgroups include oxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidinyl,dihydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, triazolidinyl,oxadiazolidinyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl,piperazinyl, tetrahydropyranyl, dioxanyl, morpholinyl, triazinanyl,azepanyl, diazepanyl, diazepinyl, oxepanyl, dioxepanyl, oxazepanyl,oxazepinyl and the like. In some embodiments, the heterocyclyl group has1 or 2 ring heteroatoms. In some embodiments, the heterocyclyl group hasfrom 5 to 6 ring atoms, 1 or 2 of which are heteroatoms.

Unless otherwise specified, each instance of an “optionally substituted”heterocyclyl group is independently unsubstituted or substituted with1-3, 1-2 or 1 substituent(s):

wherein

represents the heterocyclyl group,

-   -   and each of m4, m5 and m6 is independently 0 (i.e., R^(S[4,5,6])        is —H) or 1.    -   In some embodiments, m4+m5+m6≦2. In some embodiments,        m4+m5+m6≦1.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “fused aryl” refers to an aryl group in which two adjacent ringatoms, together with additional atoms, form a carbocycle or heterocycle(as defined with reference to “carbocyclyl” and “heterocyclyl”,respectively). Examples of fused aryl groups include1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl,2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1H-inden-4-yl,2,2-dimethyl-2,3-dihydrobenzofuran-7-yl,1,1-dimethyl-1,3-dihydroisobenzofuran-4-yl, benzo[d][1,3]dioxol-4-yl,1,2,3,4-tetrahydroquinoxalin-5-yl,2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl and the like.

Unless otherwise specified, each instance of an “optionally substituted”fused aryl group is independently unsubstituted or substituted with 1-4,1-3, 1-2 or 1 substituent(s):

wherein

represents the aryl group,

-   -   and

-   -    represents the carbocycle or heterocycle,    -   and each of m4, m5, m8 and m9 is independently 0 (i.e.,        R^(S[4,5,8,9]) is —H) or 1.    -   In some embodiments, m4+m5+m8+m9≦3. In some embodiments,        m4+m5+m8+m9≦2. In some embodiments, m4+m5+m8+m9≦1.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “fused carbocyclyl” refers to a carbocyclyl group in which twoadjacent ring atoms, together with additional atoms, form an aromatic orheteroaromatic ring (as defined with reference to “aryl” and“heteroaryl”, respectively), or in which two ring atoms, together withadditional atoms, form a heterocycle (as defined with reference to“heterocyclyl”). Examples of fused carbocyclyl groups include1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl,2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1H-inden-1-yl,5,6,7,8-tetrahydroquinolin-5-yl, 5,6,7,8-tetrahydroquinolin-7-yl,4,5,6,7-tetrahydro-1H-indol-4-yl, 4,5,6,7-tetrahydro-1H-indol-6-yl,4,5,6,7-tetrahydrobenzofuran-7-yl and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “fused heteroaryl” refers to a heteroaryl group in which twoadjacent ring atoms, together with additional atoms, form a carbocycleor heterocycle (as defined with reference to “carbocyclyl” and“heterocyclyl”, respectively). Examples of fused heteroaryl groupsinclude 4,5,6,7-tetrahydro-1H-indol-2-yl,4,5,6,7-tetrahydro-1H-indol-3-yl, 4,5,6,7-tetrahydrobenzofuran-2-yl,4,5,6,7-tetrahydrobenzofuran-3-yl, 4,5,6,7-tetrahydrobenzothiophen-2-yl,4,5,6,7-tetrahydrobenzothiophen-3-yl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridin-2-yl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridin-3-yl,1,4,5,7-tetrahydropyrano[3,4-b]pyrrol-2-yl,1,4,5,7-tetrahydropyrano[3,4-b]pyrrol-3-yl,4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl,4,5,6,7-tetrahydrofuro[3,2-c]pyridin-3-yl,6,7-dihydro-5H-furo[3,2-b]pyran-2-yl,6,7-dihydro-5H-furo[3,2-b]pyran-3-yl,4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl,4,5,6,7-tetrahydrothieno[3,2-b]pyridin-3-yl,5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl,5,7-dihydro-4H-thieno[2,3-c]pyran-3-yl and the like.

Unless otherwise specified, as used herein, alone or as part of anothergroup, “fused heterocyclyl” refers to a heterocyclyl group in which twoadjacent ring atoms, together with additional atoms, form an aromatic orheteroaromatic ring (as defined with reference to “aryl” and“heteroaryl”, respectively), or in which two ring atoms, together withadditional atoms, form a carbocycle or heterocycle (as defined withreference to “carbocyclyl” and “heterocyclyl”, respectively). Examplesof fused heterocyclyl groups include indolin-1-yl, indolin-2-yl,indolin-3-yl, tetrahydroisoindol-1-yl, tetrahydroisoindol-2-yl,dihydrobenzofuran-2-yl, dihydrobenzofuran-3-yl, dihydrobenzothien-2-yl,dihydrobenzothien-3-yl, 1,2,3,4-tetrahydroquinolin-1-yl,1,2,3,4-tetrahydroquinolin-2-yl, 1,2,3,4-tetrahydroquinolin-3-yl,1,2,3,4-tetrahydroquinolin-4-yl, chroman-2-yl, chroman-3-yl,chroman-4-yl, chromen-2-yl, chromen-3-yl, chromen-4-yl,thiochroman-3-yl, isochroman-4-yl, 1H-benzo[e][1,4]diazepin-2-yl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-yl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl,2,3-dihydrofuro[2,3-b]pyridin-3-yl,5,6-dihydro-4H-furo[3,2-b]pyrrol-6-yl,1,2,3,4-tetrahydro-1,6-naphthyridin-3-yl, decahydroquinolinyl,decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,decahydronaphthyridinyl, 2-azabicyclo[2.2.2]octan-2-yl,2-azabicyclo[2.2.2]octan-3-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl,2,5-diazabicyclo[2.2.2]octan-6-yl,3,3-dimethyl-1,3-dihydroisobenzofuran-1-yl, 2,3-dihydrobenzofuran-3-yl,6-((trifluoromethyl)thio)-2,3-dihydrobenzofuran-3-yl,2,3-dihydronaphtho[1,2-b]furan-3-yl,2,3,4,5-tetrahydrobenzo[b]-oxepin-5-yl and the like.

Unless otherwise specified—

each instance of R^(S1) is independently selected from —H, (a) halo,(zc) —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2);

each instance of R^(S2) is independently selected from —H, (a) halo, (c)—OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (h) —NO₂, (i) —CN, (j)—C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)—O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o) —O—C(O)—OR^(*4), (p)—O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and (r)—N(R^(*4))—C(O)—N(R^(*4))₂;

each instance of R^(S3) is independently selected from (a) halo, (c)—OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (h) —NO₂, (i) —CN, (j)—C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)—O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o) —O—C(O)—OR^(*4), (p)—O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4), (r)—N(R^(*4))—C(O)—N(R^(*4))₂, (aa) C₃₋₆ carbocyclyl, (cc) 5- to 6-memberedheterocyclyl, (ee) C₆ aryl and (gg) 5- to 6-membered heteroaryl; whereineach of (aa) and (cc) is optionally substituted with 1-3 groupsindependently selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1)(c) —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); and wherein each of (ee)and (gg) is optionally substituted with 1-3 groups independentlyselected from (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c)—OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4);

each instance of R^(S4) is independently selected from —H, (a) halo,(b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c) —OR^(*4), (d) —N(R^(*4))₂ and(e) —SR^(†4);

each instance of R^(S5) is independently selected from —H, (a) halo,(b1) C₁₋₄ aliphatic, (b2) R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e)—SR^(†4), (f) C₁₋₃ haloalkyl, (h) —NO₂, (i) —CN, (j) —C(O)—R^(†4), (k)—C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n)—N(R^(*4))—C(O)—R^(†4), (o) —O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q)—N(R^(*4))—C(O)—OR^(*4) and (r) —N(R^(*4))—C(O)—N(R^(*4))₂;

each instance of R^(S6) is independently selected from (a) halo, (b1)C₁₋₆ aliphatic, (b2) R^(̂6-3), (c) —OR^(*6), (d) —N(R^(*6))₂, (e)—SR^(†6), (f) C₁₋₃ haloalkyl, (h) —NO₂, (i) —CN, (j) —C(O)—R^(†6), (k)—C(O)—OR^(*6), (l) —C(O)—N(R^(*6))₂, (m) —O—C(O)—R^(†6), (n)—N(R^(*6))—C(O)—R^(†6), (o) —O—C(O)—OR^(*6), (p) —O—C(O)—N(R^(*6))₂, (q)—N(R^(*6))—C(O)—OR^(*6) (r) —N(R^(*6))—C(O)—N(R^(*6))₂, (aa) C₃₋₆carbocyclyl, (bb) -A-(C₃₋₆ carbocyclyl), (cc) 5- to 6-memberedheterocyclyl, (dd) -A-(5- to 6-membered heterocyclyl), (ee) C₆ aryl,(ff) -A-(C₆ aryl), (gg) 5- to 6-membered heteroaryl and (hh) -A-(5- to6-membered heteroaryl); wherein each instance of A is independentlyselected from C₁₋₃ alkylene, C_(0-2,0-2) heteroalkylene, —O—, —S—,—N(R^(*1))— and —C(O)—; and wherein each of (aa)-(dd) is optionallysubstituted with 1-3 groups independently selected from (a) halo, (b1)C₁₋₂ aliphatic, (b2) R^(#2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e)—SR^(†2); and wherein each of (ee)-(hh) is optionally substituted with1-3 groups independently selected from (a) halo, (b1) C₁₋₄ aliphatic,(b2) R^(#4-2), (c) —OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4);

each instance of R^(S7) is independently selected from —H, (a) halo,(b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c) —OR^(*4), (d) —N(R^(*4))₂ and(e) —SR^(†4);

each instance of R^(S8) is independently selected from —H, (a) halo,(b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e)—SR^(†4), (f) C₁₋₃ haloalkyl, (g1) C₁₋₃ haloalkoxy, (g2) C₁₋₃haloalkylthio, (h) —NO₂, (i) —CN, (j) —C(O)—R^(†4), (k) —C(O)—OR^(*4),(l) —C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4),(o) —O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4)and (r) —N(R^(*4))—C(O)—N(R^(*4))₂; and

each instance of R^(S9) is independently selected from —H, (a) halo,(b1) C₁₋₆ aliphatic, (b2) R^(̂6-3), (c) —OR^(*6), (d) —N(R^(*6))₂, (e)—SR^(†6), (f) C₁₋₃ haloalkyl, (g1) C₁₋₃ haloalkoxy, (g2) C₁₋₃haloalkylthio, (h) —NO₂, (i) —CN, (j) —C(O)—R^(†6), (k) —C(O)—OR^(*6),(l) —C(O)—N(R^(*6))₂, (m) —O—C(O)—R^(†6), (n) —N(R^(*6))—C(O)—R^(†6),(o) —O—C(O)—OR^(*6), (p) —O—C(O)—N(R^(*6))₂, (q)—N(R^(*6))—C(O)—OR^(*6), (r) —N(R^(*6))—C(O)—N(R^(*6))₂, (s)—Si(R^(†2))₃, (aa) C₃₋₈ carbocyclyl, (bb) -A-(C₃₋₈ carbocyclyl), (cc) 5-to 10-membered heterocyclyl, (dd) -A-(5- to 10-membered heterocyclyl),(ee) C₆₋₁₀ aryl, (ff) -A-(C₆₋₁₀ aryl), (gg) 5- to 10-membered heteroaryland (hh) -A-(5- to 10-membered heteroaryl); wherein each instance of Ais independently selected from C₁₋₃ alkylene, C_(0-3,0-3)heteroalkylene, —O—, —S—, —N(R^(*6))— and —C(O)—; and wherein each of(aa)-(dd) is optionally substituted with 1-3 groups independentlyselected from (a) halo, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c)—OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); and wherein each of(ee)-(hh) is optionally substituted with 1-3 groups independentlyselected from (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c)—OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4).

Each instance of

-   -   R^(*6)} {C₁₋₆ alkyl    -   R^(*4)} {C₁₋₄ alkyl    -   R^(*3)} is independently —H or {C₁₋₃ alkyl    -   R^(*2)} {C₁₋₂ alkyl    -   R^(*1)} {methyl.

Each instance of

-   -   R^(†6)} {C₁₋₆ alkyl    -   R^(†4)} {C₁₋₄ alkyl    -   R^(†3)} is independently {C₁₋₃ alkyl    -   R^(†2)} {C₁₋₂ alkyl.

As prescribed in the following table, each instance of

R{circumflex over ( )}⁶⁻³} is independently {C₁₋₆alkyl} unsubstituted or{1-3 substituent(s): R{circumflex over ( )}⁶⁻²} {C₁₋₆alkyl} substitutedwith {1-2 R{circumflex over ( )}⁶⁻¹} {C₁₋₆alkyl} {1 R{circumflex over( )}⁴⁻²} {C₁₋₄alkyl} {1-2 R{circumflex over ( )}⁴⁻¹} {C₁₋₄alkyl} {1R{circumflex over ( )}²⁻¹} {C₁₋₂alkyl} {1 1-3 1-2 1

As prescribed in the following table, each instance of

R^(#6-3)} is independently {C₁₋₆alkyl} unsubstituted or {1-3substituent(s): R^(#6-2)} {C₁₋₆alkyl} substituted with {1-2 R^(#6-1)}{C₁₋₆alkyl} {1 R^(#4-2)} {C₁₋₄alkyl} {1-2 R^(#4-1)} {C₁₋₄alkyl} {1R^(#2-1)} {C₁₋₂alkyl} {1 1-3 1-2 1

In each of these groups, when a subgroup is designating with a multipleoccurrence, each occurrence is selected independently. For example, in—N(R^(*6))₂, the R^(*6) groups can be the same or different.

The following common names and abbreviations for various radicals areemployed throughout.

methyl Me —CH₃ ethyl Et —CH₂CH₃ propyl Pr —CH₂CH₂CH₃ isopropyl ^(i)Pr

butyl Bu —CH₂CH₂CH₂CH₃ isobutyl ^(i)Bu

sec-butyl ^(s)Bu

tert-butyl ^(t)Bu

phenyl Ph

benzyl Bn

Chemical Entities

Unless otherwise stated, structures depicted herein are meant to includechemical entities which differ only in the presence of one or moreisotopically enriched atoms. For example, chemical entities having thepresent structure except for the replacement of a hydrogen atom by adeuterium or tritium, or the replacement of a carbon atom by a ¹³C- or¹⁴C-enriched carbon are within the scope of the invention.

Unless stereochemical configuration is denoted, structures depictedherein are meant to include all stereochemical forms of the structure,i.e., the R and S configurations for each asymmetric center. Therefore,unless otherwise indicated, single stereochemical isomers as well asenantiomeric, racemic and diastereomeric mixtures of the presentchemical entities are within the scope of the invention. As furtherclarification of the nomenclature used to describe the compoundsexemplified in the invention, a compound such as the one with the name“(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(naphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate” describes a racemic mixture of both“((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(naphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate” and“((1S,2S,3R,4S)-2,3-dihydroxy-4-(2-(naphthaen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate” whereas, for example“(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylsulfamate” denotes the single enantiomer of the compound with thespecified stereochemical assignment.

As used herein, “crystalline” refers to a solid in which the constituentatoms, molecules, or ions are packed in a regularly ordered, repeatingthree-dimensional pattern having a highly regular chemical structure. Inparticular, a crystalline compound or salt might be produced as one ormore crystalline forms. For the purposes of this application, the terms“crystalline form” and “polymorph” are synonymous; the terms distinguishbetween crystals that have different properties (e.g., different XRPDpatterns, different DSC scan results). Pseudopolymorphs are typicallydifferent solvates of a material, and thus the properties ofpseudopolymorphs differ from one another. Thus, each distinct polymorphand pseudopolymorph is considered to be a distinct crystalline formherein.

“Substantially crystalline” refers to compounds or salts that are atleast a particular weight percent crystalline. In some embodiments, thecompound or salt is substantially crystalline. Examples of a crystallineform or substantially crystalline form include a single crystalline formor a mixture of different crystalline forms. Particular weightpercentages include 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%. In someembodiments, substantially crystalline refers to compounds or salts thatare at least 70% crystalline. In some embodiments, substantiallycrystalline refers to compounds or salts that are at least 80%crystalline. In some embodiments, substantially crystalline refers tocompounds or salts that are at least 85% crystalline. In someembodiments, substantially crystalline refers to compounds or salts thatare at least 90% crystalline. In some embodiments, substantiallycrystalline refers to compounds or salts that are at least 95%crystalline.

Representative solvates include, for example, hydrates, ethanolates, andmethanolates.

The term “hydrate” refers to a solvate wherein the solvent molecule isH₂O that is present in a defined stoichiometric amount, and includes,for example, hemihydrates, monohydrates, dihydrates, and trihydrates.

The term “seeding” refers to the addition of crystalline material to asolution or mixture to initiate crystallization.

Some embodiments of the invention are directed to compounds or saltswherein at least a particular percentage by weight of the compound orsalt is crystalline. Some embodiments of the invention are directed to acompound or salt wherein at least a particular percentage by weight ofthe compound or salt is crystalline. Particular weight percentagesinclude 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% and 99.9%. Whena particular percentage by weight of the compound or salt iscrystalline, the remainder of the compound or salt is the amorphous formof the compound or salt. When a particular percentage by weight of thecompound or salt is a designated crystalline form, the remainder of thecompound or salt is some combination of the amorphous form of thecompound or salt, and one or more crystalline forms of the compound orsalt excluding the designated crystalline form.

When a crystalline form of a compound or salt is identified using one ormore XRPD peaks given as angles 2θ, each of the 2θ values is understoodto mean the given value ±0.2 degrees, unless otherwise expressed, forexample as the given value ±0.3.

When a crystalline form of a compound or salt is identified using one ormore temperatures from a DSC profile (e.g., onset of endothermictransition, melt, etc.), each of the temperature values is understood tomean the given value ±2° C.

When a crystalline form of a compound or salt is identified using one ormore peaks from a raman pattern expressed as cm⁻¹, it is understood tomean the given value ±0.2 cm⁻¹, unless otherwise expressed.

Each chemical entity of the present invention is a compound of FormulaI:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   W is —N(R^(*3))—;    -   Y is

-   -   each of R^(Y1), R^(Y2) and R^(Y3) is independently selected from        —H, (a) halo, (b1) C₁₋₃ aliphatic, (b2) R^(#2-1), (c)        —OR^(*3), (d) —N(R^(*3))₂, (e) —SR^(†3), (f) C₁₋₂ haloalkyl        and (g) C₁₋₂ haloalkoxy;    -   Z is        -   (1) optionally substituted aryl:

-   -   -    wherein

-   -   -    represents the aryl group;        -   (2) optionally substituted fused aryl:

-   -   -    wherein

-   -   -    represents the aryl group,            -   and

-   -   -   -    represents the carbocycle Het or heterocycle;

        -   (3) optionally substituted heteroaryl:

-   -   -    wherein

-   -   -    represents the heteroaryl group;            -   or        -   (4)

-   -   -    wherein

    -   X⁴ is —O—, —N(R^(*3))—, —S— or —C(O)—; and

    -   each of n1 and n2 is independently 0, 1 or 2, provided that        n1+n2=0, 1 or 2.

In some embodiments, W is —N(R^(*1))—. In some embodiments, W is —NH—.

In some embodiments, each of R^(Y1), R^(Y2) and R^(Y3) is independentlyselected from —H, (a) halo and (b1) C₁₋₃alkyl. In some embodiments, eachof R^(Y1), R^(Y2) and R^(Y3) is independently selected from —H, (a) —F,—Cl and (b1) methyl. In some embodiments, each of R^(Y1), R^(Y2) andR^(Y3) is —H.

In some embodiments, Z is optionally substituted aryl.

In some embodiments, Z is optionally substituted phenyl:

wherein

represents phenyl,

-   -   each of R^(S7.1a) and R^(S7.1b) is independently selected from        —H, (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c)        —OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4);    -   R^(S8.1) is selected from —H, (a) halo, (b1) C₁₋₄ aliphatic,        (b2) R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f)        C₁₋₃ haloalkyl, (g1) C₁₋₃ haloalkoxy, (g2) C₁₋₃        haloalkylthio, (h) —NO₂, (i) —CN, (j) —C(O)—R^(†4), (k)        —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n)        —N(R^(*4))—C(O)—R^(†4), (o) —O—C(O)—OR^(*4), (p)        —O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and (r)        —N(R^(*4))—C(O)—N(R^(*4))₂; R^(S9.1) is selected from —H, (a)        halo, (b1) C₁₋₆ aliphatic, (b2) R^(̂6-3), (c) —OR^(*6), (d)        —N(R^(*6))₂, (e) —SR^(†6), (f) C₁₋₃ haloalkyl, (g1) C₁₋₃        haloalkoxy, (g2) C₁₋₃ haloalkylthio, (h) —NO₂, (i) —CN, (j)        —C(O)—R^(†6), (k) —C(O)—OR^(*6), (l) —C(O)—N(R^(*6))₂, (m)        —O—C(O)—R^(†6), (n) —N(R^(*6))—C(O)—R^(†6), (o)        —O—C(O)—OR^(*6), (p) —O—C(O)—N(R^(*6))₂, (q)        —N(R^(*6))—C(O)—OR^(*6), (r) —N(R^(*6))—C(O)—N(R^(*6))₂, (s)        —Si(R^(†2))₃, (aa) C₃₋₈ carbocyclyl, (bb) -A-(C₃₋₈        carbocyclyl), (cc) 5- to 10-membered heterocyclyl, (dd) -A-(5-        to 10-membered heterocyclyl), (ee) C₆₋₁₀ aryl, (ff) -A-(C₆₋₁₀        aryl), (gg) 5- to 10-membered heteroaryl and (hh) -A-(5- to        10-membered heteroaryl); wherein A is selected from C₁₋₃        alkylene, C_(0-3,0-3) heteroalkylene, —O—, —S—, —N(R^(*1))— and        —C(O)—; and wherein each of (aa)-(dd) is optionally substituted        with 1-3 groups independently selected from (a) halo, (b1) C₁₋₂        aliphatic, (b2) R^(#2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e)        —SR^(†2); and wherein each of (ee)-(hh) is optionally        substituted with 1-3 groups independently selected from (a)        halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c) —OR^(*4), (d)        —N(R^(*4))₂ and (e) —SR^(†4).

In some embodiments, at least 1 of R^(S7.1a), R^(S7.1b), R^(S8.1) andR^(S9)1 is —H. In some embodiments, at least 2 of R^(S7.1a), R^(S7.1b),R^(S8.1) and R^(S9.1) are —H.

In some embodiments, R^(S9.1) is selected from —H, (a) halo, (b1) C₁₋₆aliphatic, (b2) R^(̂6-3), (c) —OR^(*6), (d) —N(R^(*6))₂, (e) —SR^(†6),(f) C₁₋₃ haloalkyl, (g1) C₁₋₃ haloalkoxy, (g2) C₁₋₃ haloalkylthio, (h)—NO₂, (i) —CN, (j) —C(O)—R^(†6), (k) —C(O)—OR^(*6), (l)—C(O)—N(R^(*6))₂, (m) —O—C(O)—R^(†6) (n) —N(R^(*6))—C(O)—R^(†6), (o)—O—C(O)—OR^(*6), (p) —O—C(O)—N(R^(*6))₂, (q) —N(R^(*6))—C(O)—OR^(*6),(r) —N(R^(*6))—C(O)—N(R^(*6))₂, (s) —Si(R^(†2))₃, (aa) C₃₋₆ carbocyclyl,(bb) -A-(C₃₋₆ carbocyclyl), (cc) 5- to 6-membered heterocyclyl, (dd)-A-(5- to 6-membered heterocyclyl), (ee) C₆₋₁₀ aryl, (ff) -A-(C₆₋₁₀aryl), (gg) 5- to 10-membered heteroaryl and (hh) -A-(5- to 10-memberedheteroaryl); wherein A is selected from C₁₋₃ alkylene, C_(0-2,0-2)heteroalkylene, —O—, —S—, —N(R^(*6))— and —C(O)—; and wherein each of(aa)-(dd) is optionally substituted with 1-2 groups independentlyselected from (a) halo, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c)—OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); and wherein each of(ee)-(hh) is optionally substituted with 1-3 groups independentlyselected from (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c)—OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4).

In some embodiments, each of (aa)-(dd) is optionally substituted with 1group selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c)—OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); and each of (ee)-(hh) isoptionally substituted with 1-2 groups independently selected from (a)halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c) —OR^(*4), (d) —N(R^(*4))₂and (e) —SR^(†4).

In some embodiments, each of R^(S8.1) and R^(S9.1) is independentlyselected from —H, (a) —F, —Cl, (b1) C₁₋₂ alkyl, (c) —OR^(*2), (d)—N(R^(*2))₂, (e) —SR^(†2), (f) —CF₃, (g1) —O—CF₃ and (g2) —S—CF₃. Insome embodiments, each of R^(S8.1) and R^(S9.1) is independentlyselected from —H, (a) —F, —Cl, (b1) —CH₃, (c) —OMe, (f) —CF₃, (g1)—O—CF₃ and (g2) —S—CF₃.

In some embodiments, R^(S7.b) is —H. In some embodiments, each ofR^(S7.a) and R^(S7.1b) is —H.

In some embodiments, R^(S9.1) is selected from —H, (a) halo, (b1) C₁₋₄aliphatic, (b2) R^(#6-3), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4),(f) C₁₋₃ haloalkyl, (g1) C₁₋₃ haloalkoxy, (g2) C₁₋₃ haloalkylthio, (h)—NO₂, (i) —CN, (j) —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l)—C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)—O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4),(r) —N(R^(*4))—C(O)—N(R^(*4))₂, (s) —Si(R^(†2))₃, (aa) C₃₋₆ carbocyclyl,(bb) -A-(C₃₋₆ carbocyclyl), (cc) 5- to 6-membered heterocyclyl, (dd)-A-(5- to 6-membered heterocyclyl), (ee) C₆ aryl, (ff) -A-(C₆ aryl),(gg) 5- to 6-membered heteroaryl and (hh) -A-(5- to 6-memberedheteroaryl); wherein A is selected from C₁₋₃ alkylene, C_(0-2,0-2)heteroalkylene, —O—, —S—, —N(R^(*1))— and —C(O)—; and wherein each of(aa)-(dd) is optionally substituted with 1 group selected from (a) halo,(b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and(e) —SR^(†2); and wherein each of (ee)-(hh) is optionally substitutedwith 1-2 groups independently selected from (a) halo, (b1) C₁₋₄aliphatic, (b2) R^(#4-2) (c) —OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4);and

-   -   R^(#6-3) is

-   -    wherein

-   -    represents C₁₋₆ alkyl; and        -   each of m1, m2 and m3 is independently 0 or 1.

In some embodiments, R^(S9.1) is selected from —H, (a) halo, (b1) C₁₋₄aliphatic, (b2) R^(#6-3), (c) —OR^(*4), (f) C₁₋₃ haloalkyl, (g1) C₁₋₃haloalkoxy, (g2) C₁₋₃ haloalkylthio, (s) —Si(R^(†2))₃, (aa) C₃₋₆carbocyclyl, (bb) -A-(C₃₋₆ carbocyclyl), (cc) 5- to 6-memberedheterocyclyl, (ee) C₆ aryl, (ff) -A-(C₆ aryl) and (gg) 5- to 6-memberedheteroaryl; wherein A is selected from —CH₂—, C_(0-1,0-1)heteroalkylene, —O—, —S—, —NH— and —C(O)—; and wherein each of (aa)-(cc)is optionally substituted with 1 group selected from (a) halo, (b1) C₁₋₂aliphatic, (b2) R^(#2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e)—SR^(†2); and wherein each of (ee)-(gg) is optionally substituted with 1group selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c)—OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2). In some embodiments,R^(S9.1) is selected from —H, (a) —Cl, —Br, (b1) ^(t)Bu, —C≡C, (b2)—C(CH₃)₂—CF₃, —C(CH₃)₂—O-Me, —C(CH₃)₂—O-Et, —C(CH₃)₂—O—Pr,—C(CH₃)(CH₂—OH)(CH₂—Cl), (c) —OMe, (f) —CF₃, (g1) —O—CHF₂, —O—CF₃, (g2)—S—CF₃, (s) —Si(CH₃)₃, (aa) cyclopentyl, cyclopenten-1-yl, (bb)—S-cyclopropylmethyl, (cc) pyrrolidin-1-yl, piperidin-1-yl,pyrrolidin-2-on-1-yl, morpholin-4-yl, (ee) phenyl, (ff) benzyl, —O-Ph,—C(O)-Ph, (gg) pyridin-2-yl and 1-methyl-1H-pyrazol-2-yl.

In some embodiments, R^(S8.1) is selected from —H, (a) halo, (b1) C₁₋₂aliphatic, (b2) R^(̂2-1), (c) —OR^(*2), (d) —N(R^(*2))₂, (e) —SR^(†2),(f) C₁₋₃ haloalkyl, (g1) C₁₋₃ haloalkoxy, (g2) C₁₋₃ haloalkylthio, (h)—NO₂, (i) —CN, (j) —C(O)—R^(†2), (k) —C(O)—OR^(*2), (l)—C(O)—N(R^(*2))₂, (m) —O—C(O)—R^(†2), (n) —N(R^(*2))—C(O)—R^(†2), (o)—O—C(O)—OR^(*2), (p) —O—C(O)—N(R^(*2))₂, (q) —N(R^(*2))—C(O)—OR^(*2) and(r) —N(R^(*2))—C(O)—N(R^(*2))₂. In some embodiments, R^(S8.1) is —H.

In some embodiments, R^(S7.1b) is —H; and R^(S8.1) is —H. In someembodiments, each of R^(S7.1a) and R^(S7.1b) is —H; and R^(S8.1) is —H.

In some embodiments, Z is optionally substituted naphthyl:

wherein

represents naphthyl;

-   -   each of R^(S7.1a) and R^(S7.1b) is independently selected        from (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c)        —OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4);    -   R^(S8.1) is selected from (a) halo, (b1) C₁₋₄ aliphatic, (b2)        R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f) C₁₋₃        haloalkyl, (g) C₁₋₃ haloalkoxy, (h) —NO₂, (i) —CN, (j)        —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)        —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)        —O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q)        —N(R^(*4))—C(O)—OR^(*4) and (r) —N(R^(*4))—C(O)—N(R^(*4))₂;    -   R^(S9.1) is selected from (a) halo, (b1) C₁₋₄ aliphatic, (b2)        R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f) C₁₋₃        haloalkyl, (g) C₁₋₃ haloalkoxy, (h) —NO₂, (i) —CN, (j)        —C(O)—R^(†4) (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)        —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)        —O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q)        —N(R^(*4))—C(O)—OR^(*4) and (r) —N(R^(*4))—C(O)—N(R^(*4))₂, (aa)        C₃₋₆ carbocyclyl, (cc) 5- to 6-membered heterocyclyl, (ee) C₆        aryl and (gg) 5- to 6-membered heteroaryl; wherein each of (aa)        and (cc) is optionally substituted with 1-2 groups independently        selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c)        —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); and wherein each of        (ee) and (gg) is optionally substituted with 1-3 groups        independently selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2)        R^(#2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2);    -   provided that at least 1 of R^(S7.1a), R^(S7.1b), R^(S8.1) and        R^(S9.1) is —H.

In some embodiments, at least 2 of R^(S7.1a), R^(S7.1b), R^(S8.1) andR^(S9.1) are —H.

In some embodiments, R^(S9.1) is selected from (a) halo, (b1) C₁₋₄aliphatic, (b2) R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4),(f) C₁₋₃ haloalkyl, (g) C₁₋₃ haloalkoxy, (h) —NO₂, (i) —CN, (j)—C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)—O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o) —O—C(O)—OR^(*4), (p)—O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and (r)—N(R^(*4))—C(O)—N(R^(*4))₂.

In some embodiments, R^(S7.1a) is —H; and R^(S7.1b) is selected from —H,(a) halo and (b1) C₁₋₂ aliphatic.

In some embodiments, each of R^(S7.1a) and R^(S7.1b) is —H; R^(S8.1) isselected from —H, (a) halo and (b1) C₁₋₂ aliphatic; and R^(S9.1) isselected from (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(̂4-2), (c) —OR^(*4),(d) —N(R^(*4))₂, (e) —SR^(†4), (f) C₁₋₃ haloalkyl, (g) C₁₋₃ haloalkoxy,(h) —NO₂, (i) —CN, (j) —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l)—C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)—O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and(r) —N(R^(*4))—C(O)—N(R^(*4))₂. In some embodiments, each of R^(S7.1a)and R^(S7.1b) is —H; R^(S8.1) is —H; and R^(S9.1) is selected from (a)—F, —Cl, (b1) C₁₋₂ alkyl, (c) —OR^(*4), (d) —N(R^(*2))₂, (f) C₁₋₂haloalkyl, (g) C₁₋₂ haloalkoxy and (k) —C(O)—OR^(*2). each of R^(S7.1a)and R^(S7.1b) is —H; and each of R^(S8.1) and R^(S9.1) is independentlyselected from —H, (a) halo and (b1) C₁₋₂ aliphatic. In some embodiments,each of R^(S7.1a) and R^(S7.1b) is —H; and each of R^(S8.1) and R^(S9.1)is independently selected from —H, (a) —F and —Cl.

In some embodiments, Z is optionally substituted fused aryl:

wherein

represents the aryl group,

-   -   and

-   -    represents the carbocycle or heterocycle;    -   R^(S4.2) is selected from —H, (a) halo, (b1) C₁₋₄ aliphatic,        (b2) R^(#4-2), (c) —OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4);    -   R^(S5.2) is selected from —H, (a) halo, (b1) C₁₋₄ aliphatic,        (b2) R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f)        C₁₋₃ haloalkyl, (h) —NO₂, (i) —CN, (j) —C(O)—R^(†4), (k)        —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n)        —N(R^(*4))—C(O)—R^(†4), (o) —O—C(O)—OR^(*4), (p)        —O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and (r)        —N(R^(*4))—C(O)—N(R^(*4))₂;    -   R^(S8.2) is selected from —H, (a) halo, (b1) C₁₋₄ aliphatic,        (b2) R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f)        C₁₋₃ haloalkyl, (g) C₁₋₃ haloalkoxy, (h) —NO₂, (i) —CN, (j)        —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)        —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)        —O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q)        —N(R^(*4))—C(O)—OR^(*4) and (r) —N(R^(*4))—C(O)—N(R^(*4))₂;    -   R^(S9.2) is selected from —H, (a) halo, (b1) C₁₋₄ aliphatic,        (b2) R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f)        C₁₋₃ haloalkyl, (g) C₁₋₃ haloalkoxy, (h) —NO₂, (i) —CN, (j)        —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)        —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)        —O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q)        —N(R^(*4))—C(O)—OR^(*4) and (r) —N(R^(*4))—C(O)—N(R^(*4))₂, (aa)        C₃₋₆ carbocyclyl, (cc) 5- to 6-membered heterocyclyl, (ee) C₆        aryl and (gg) 5- to 6-membered heteroaryl; wherein each of (aa)        and (cc) is optionally substituted with 1-2 groups independently        selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c)        —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); and wherein each of        (ee) and (gg) is optionally substituted with 1-3 groups        independently selected from (a) halo, (b1) C₁₋₄ aliphatic, (b2)        R^(#4-2), (c) —OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4).

In some embodiments, the aryl group is a C₆ aryl group; the carbocycleis a C₅₋₆ carbocycle; and the heterocycle is a 5- to 6-memberedheterocycle having one ring heteroatom selected from —O—, —N(R^(*1))—and —S—. In some embodiments, the carbocycle is a saturated C₅₋₆carbocycle; and the heterocycle is a saturated 5- to 6-memberedheterocycle wherein the ring heteroatom is —O—. In some embodiments, Zis optionally substituted indanyl, 2,3-dihydrobenzofuranyl or1,3-dihydroisobenzofuranyl.

In some embodiments, R^(S4.2) is selected from —H, (a) —F, Cl, (b1) C₁₋₂aliphatic, (b2) R^(̂2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2);R^(S5.2) is selected from —H, (a) halo, (b1) C₁₋₂ aliphatic, (b2)R^(̂2-1), (c) —OR^(*2), (d) —N(R^(*2))₂, (e) —SR^(†2) and (f) —CF₃;R^(S8.2) is —H; and R^(S9.2) is selected from —H, (a) —F, Cl, (b1) C₁₋₂aliphatic, (b2) R^(̂2-1), (c) —OR^(*2), (d) —N(R^(*2))₂, (e) —SR^(†2),(f) —CF₃ and (g) —OCF₃. In some embodiments, each of R^(S4.2) andR^(S5.2) is independently selected from —H, (b1) C₁₋₂ aliphatic and (b2)R^(̂2-1); and each of R^(S8.2) and R^(S9.2) is —H. In some embodiments,each of R^(S4.2) and R^(S5.2) is methyl; and each of R^(S8.2) andR^(S9.2) is —H.

In some embodiments, wherein Z is optionally substituted heteroaryl:

wherein

represents the heteroaryl group;

-   -   each of R^(S7.3a) and R^(S7.3b) is independently selected        from (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c)        —OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4);    -   R^(S8.3) is selected from (a) halo, (b1) C₁₋₄ aliphatic, (b2)        R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f) C₁₋₃        haloalkyl, (g) C₁₋₃ haloalkoxy, (h) —NO₂, (i) —CN, (j)        —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)        —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)        —O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q)        —N(R^(*4))—C(O)—OR^(*4) and (r) —N(R^(*4))—C(O)—N(R^(*4))₂;    -   R^(S9.3) is selected from (a) halo, (b1) C₁₋₄ aliphatic, (b2)        R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f) C₁₋₃        haloalkyl, (g) C₁₋₃ haloalkoxy, (h) —NO₂, (i) —CN, (j)        —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)        —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)        —O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q)        —N(R^(*4))—C(O)—OR^(*4) and (r) —N(R^(*4))—C(O)—N(R^(*4))₂, (aa)        C₃₋₆ carbocyclyl, (cc) 5- to 6-membered heterocyclyl, (ee) C₆        aryl and (gg) 5- to 6-membered heteroaryl; wherein each of (aa)        and (cc) is optionally substituted with 1-2 groups independently        selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c)        —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); and wherein each of        (ee) and (gg) is optionally substituted with 1-3 groups        independently selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2)        R^(#2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2);    -   provided that at least 1 of R^(S7.3a), R^(S7.3b), R^(S8.3) and        R^(S9.3) is —H.

In some embodiments, Z is optionally substituted 5- to 10-memberedheteroaryl having 1 or 2 ring heteroatoms, each independently selectedfrom O, S and NR^(*3). In some embodiments, Z is optionally substitutedthienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, benzo[b]thiophenyl,benzofuranyl, 1H-indolyl, quinolinyl or isoquinolinyl.

In some embodiments, at least 2 of R^(S7.3a), R^(S7.3b), R^(S8.3) andR^(S9.3) are —H.

In some embodiments, R^(S7.3a) is —H; and R^(S8.3) is selected from —H,(a) halo, (b1) C₁₋₄ aliphatic and (f) C₁₋₃ haloalkyl.

In some embodiments, R^(S7.3a) is —H; R^(S7.3b) is —H; R^(S8.3) isselected from —H, (a) halo, (b1) C₁₋₄ aliphatic and (f) C₁₋₃ haloalkyl;and R^(S9.3) is selected from —H, (a) halo, (b1) C₁₋₄ aliphatic, (f)C₁₋₃ haloalkyl and (ee) phenyl. In some embodiments, R^(S8.3) isselected from —H, (a) halo, (b1) C₁₋₂ alkyl and (f) —CF₃. In someembodiments, R^(S7.3a) is —H; R^(S7.3b) is —H; R^(S8.3) is —H or (b1)methyl; and R^(S9.3) is selected from —H, (a) halo, (b1) C₁₋₄ alkyl, (f)C₁₋₃ haloalkyl and (ee) phenyl. In some embodiments, R^(S9.3) isselected from —H, (a) —F, —Cl, (b1) methyl, ethyl, ^(t)Bu (f) —CF₃ and(ee) phenyl.

In some embodiments, each of R^(S7.3a) and R^(S7.3b) is —H; and R^(S8.3)is —H.

In some embodiments, Z is

wherein

-   -   X⁴ is —O—, —N(R^(*2))—, —S— or —C(O)—;    -   each of n1 and n2 is independently 0, 1 or 2, provided that        n1+n2=0, 1 or 2; and    -   each instance of R^(S7.4) is independently selected from (a)        halo, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c) —OR^(*2), (d)        —N(R^(*2))₂ and (e) —SR^(†2).

In some embodiments, each instance of R^(S7.4) is independently selectedfrom (a) —F, —Cl, —Br, (b1) C₁₋₂ aliphatic, (b2) R^(#2-1), (c) —OR^(*2)and (d) —N(R^(*2))₂, wherein each instance of R^(#2-1) is independentlyC₁₋₂ alkyl unsubstituted or substituted with 1 substituent selected from(a) —F, —Cl, (c) —OR^(*2) and (d) —N(R^(*2))₂.

In some embodiments, X⁴ is —O—, —NH—, —S— or —C(O)—.

In some embodiments, n1+n2=1. In some embodiments, each of n1 and n2 is0.

Examples of compounds of the chemical entities of the present inventioninclude those listed in the following tables.

I-001

I-002

I-003

I-004

I-005

I-006

I-007

I-008

I-009

I-010

I-011

I-012

I-013

I-014

I-015

I-016

I-017

I-018

I-019

I-020

I-021

I-022

I-023

I-024

I-025

I-026

I-027

I-028

I-029

I-030

I-031

I-032

I-033

I-034

I-035

I-036

I-037

I-038

I-039

I-040

I-041

I-042

I-043

I-044

I-045

I-046

I-047

I-048

I-049

I-050

I-051

I-052

I-053

I-054

I-055

I-056

I-057

I-058

I-059

I-060

I-061

I-062

I-063

I-064

I-065

I-066

I-067

I-068

I-069

I-070

I-071

I-072

I-073

I-074

I-075

I-076

I-077

I-078

I-079

I-080

I-081

I-082

I-083

I-084

I-085

I-086

I-087

I-088

I-089

I-090

I-091

I-092

I-093

I-094

I-095

I-096

I-097

I-098

I-099

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

cpd no. compound name I-001(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-phenylpyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-002(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methyl rel-sulfamate I-003(rac)((1R,2R,3S,4R)-4-(2-(biphenyl-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-004(rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl}methyl rel-sulfamate I-005(rac)-((1R,2R,3S,4R)-4-((2-(3-Chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-006(rac)-{(1R,2R,3S,4R)-4-[(5-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methyl rel-sulfamate I-007(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl rel-sulfamate I-008(rac)-((1R,2R,3S,4R)-4-(2-(4-bromophenyl)-5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-009(rac)-((1R,2R,3S,4R)-4-{[5-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-010(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-011(rac)-((1R,2R,3S,4R)-4-(5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-012(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate I-013(rac)-[(1R,2R,3S,4R)-4-{[2-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate I-014(rac)-[(1R,2R,3S,4R)-4-{[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate I-015(rac)-((1R,2R,3S,4R)-4-((2-(3-(tert-Butyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-016(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(naphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-017(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(quinolin-8-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl rel-sulfamate I-018(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(isoquinolin-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-019(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-020(rac)-((1R,2R,3S,4R)-4-(2-(5-chloro-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-021(rac)-((1R,2R,3S,4R)-4-(2-(5-chloro-2-methylphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-022(rac)-((1R,2R,3S,4R)-4-(2-(benzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-023(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamateI-024(rac)-((1R,2R,3S,4R)-4-(2-(1H-indol-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-025(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-026(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamateI-027(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(isoquinolin-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-028(rac)-((1R,2R,3S,4R)-4-((2-(3-Bromophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-029(rac)-((1R,2R,3S,4R)-4-((2-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamateI-030(rac)-((1R,2R,3S,4R)-4-((2-(2-Chloro-5-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamateI-031(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(4-phenyl-1,3-thiazol-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate I-032(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate I-033(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(5-(trifluoromethyl)quinolin-8-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamateI-034(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-035(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trimethylsilyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-036(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(3-(pyridin-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl rel-sulfamate I-037(rac)-[(1R,2R,3S,4R)-4-{[2-(9H-carbazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate I-038(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamateI-039(rac)-((1R,2R,3S,4R)-4-(2-(7-chloroquinolin-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-040(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl rel-sulfamate I-041(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamateI-042(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-043(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-7-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-044(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-045(rac)-((1R,2R,3S,4R)-4-((2-(Benzo[b]thiophen-7-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-046(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-047(rac)-(1R,2R,3S,4R)-4-(2-(3-cyclopentenylphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-048(rac)-[(1R,2R,3S,4R)-4-{[2-(3-cyclopentylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate I-049(rac)-((1R,2R,3S,4R)-4-(2-(benzofuran-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-050(rac)-((1R,2R,3S,4R)-4-((2-(3-(Difluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-051(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(3-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl rel-sulfamate I-052(rac)-((1R,2R,3S,4R)-4-(2-(6-tert-butylpyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-053(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-1,3-dihydroisobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel- sulfamate I-054(rac)-[(1R,2R,3S,4R)-4-{[2-(5-chloro-1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate I-055(rac)-[(1R,2R,3S,4R)-4-{[2-(6-chloro-1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate I-056(rac)-((1R,2R,3S,4R)-4-((2-(Dibenzo[b,d]thiophen-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-057(rac)-((1R,2R,3S,4R)-4-(2-(5-chloro-2-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamateI-058(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate I-059(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-(trifluoromethyl)pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamateI-060(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(5-(trifluoromethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl rel-sulfamateI-061(rac)-((1R,2R,3S,4R)-4-((2-(Benzo[b]thiophen-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-062(rac)-[(1R,2R,3S,4R)-4-{[2-(9H-carbazol-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate I-063(rac)-((1R,2R,3S,4R)-4-{[2-(5-tert-butyl-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-064(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(6-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamateI-065(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(2-methoxy-5-(trifluoromethyl)phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl rel-sulfamateI-066(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(2-methoxy-5-(trifluoromethoxy)-phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methylrel-sulfamate I-067(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(2-phenyl-1,3-oxazol-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate I-068(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-069(rac)-((1R,2R,3S,4R)-4-(2-(3-benzylphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-070(rac)-((1R,2R,3S,4R)-4-(2-(4-fluoro-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-071(rac)-((1R,2R,3S,4R)-4-(2-(5-chlorobenzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-072(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-073(rac)-((1R,2R,3S,4R)-4-(2-(3-benzoylphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-074(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1H-indol-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methyl rel-sulfamate I-075(rac)-((1R,2R,3S,4R)-4-(2-(1H-indol-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-076(rac)-((1R,2R,3S,4R)-4-(2-(3-(cyclopropylmethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamateI-077(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(piperidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-078(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-079(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-080(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(4-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-081(rac)-((1R,2R,3S,4R)-4-(2-(5-fluorobenzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-082(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(2-methoxypropan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate I-083(rac)-[(1R,2R,3S,4R)-4-{[2-(3-ethynylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl rel-sulfamate I-084(rac)-((1R,2R,3S,4R)-4-(2-(3-(2-ethoxypropan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-085(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(9-oxo-9H-fluoren-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl rel-sulfamate I-086(rac)-((1R,2R,3S,4R)-4-(2-(benzofuran-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-087(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(2-oxopyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate I-088(rac)-((1R,2R,3S,4R)-4-(2-(6-chlorobenzo[b]thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-089(rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl}methyl rel-sulfamate I-090(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(2-propoxypropan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate I-091(rac)-((1R,2R,3S,4R)-4-(2-(6-chlorobenzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-092(rac)-((1R,2R,3S,4R)-4-(2-(5-chlorobenzofuran-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-093(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-094(rac)-((1R,2R,3S,4R)-4-(2-(5-ethylbenzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-095(rac)-((1R,2R,3S,4R)-4-(2-(5-ethylbenzo[b]thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-096(rac)-methyl rel-5-[7-({(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl}amino)pyrazolo[1,5-a]pyrimidin-2-yl]-2-naphthoate I-097(rac)-((1R,2R,3S,4R)-4-(2-(5-fluoronaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-098(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methyl sulfamate I-099(rac)-rel-5-[7-({(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl}amino)pyrazolo[1,5-a]pyrimidin-2-yl]-2-naphthoicacid I-100(s.e.)-((1R,2R,3S,4R)-4-(2-(4-fluoronaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-101(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate I-102(s.e)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-({2-[2-methoxy-5-(trifluoromethoxy)-phenyl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclopentyl]methyl sulfamateI-103(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl rel-sulfamate I-104(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-methoxynaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate I-105(s.e.)-((1R,2R,3S,4R)-4-(2-(5-fluoronaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-106(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(4-methoxynaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate I-107(s.e.)-((1R,2R,3S,4R)-4-(2-(4-(dimethylamino)naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-108(s.e.)-[(1R,2R,3S,4R)-4-{[2-(4-chloro-1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methyl sulfamate I-109(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-isopropoxynaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate I-110(s.e.)-((1R,2R,3S,4R)-4-(2-(2-(difluoromethoxy)naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-111(s.e.)-((1R,2R,3S,4R)-4-(2-(6-(difluoromethyl)naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-112(s.e.)-((1R,2R,3S,4R)-4-(2-(4-(difluoromethoxy)naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-113(s.e.)-((1R,2R,3S,4R)-4-(2-(6-fluoronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-114(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-methylnaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate I-115(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(4-methylnaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate I-116(s.e.)-((1R,2R,3S,4R)-4-(2-(3-fluoronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-117(s.e.)-((1R,2R,3S,4R)-4-(2-(2,4-dichloronaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-118(s.e.)-((1R,2R,3S,4R)-4-(2-(4-fluoronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-119(s.e.)-((1R,2R,3S,4R)-4-(2-(1-fluoronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methyl sulfamate I-120(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-methoxy-5-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamateI-121(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(6-phenylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methyl rel-sulfamate I-122(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-({2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclopentyl]methylrel-sulfamate I-123(rac)-{(1R,2R,3S,4R)-4-[(2-{3-[2-chloro-1-(hydroxymethyl)-1-methylethyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyljmethyl rel-sulfamate I-124(s.e.)-{(1R,2R,3S,4R)-4-[(3,6-dichloro-2-{3-[(trifluoromethyl)sulfanyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methyl sulfamate I-125(s.e.)-{(1R,2R,3S,4R)-4-[(6-chloro-2-{3-[(trifluoromethyl)sulfanyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methyl sulfamate

General Synthetic Methods

These and other compounds of the chemical entities of the presentinvention can be prepared by methods known to one of ordinary skill inthe art and/or by reference to the schemes shown below and/or byreference to the procedures described in the Examples below.

A general route for the synthesis of compounds represented by structureiv wherein Z is an optionally substituted fused or non-fused aryl orheteroaryl ring is outlined above in Scheme 1. Compound i (obtained bycoupling an appropriately protected cyclopentylamine or salt thereofwith 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine in the presence of asuitable base as described below in the procedure of Examples 1a and 1b)is transformed to a compound of formula iii by coupling with a metalsubstituted compound Z-M via a palladium catalyzed reaction. A compoundof formula iii can also be obtained by first transforming i to a metalsubstituted compound of formula ii using suitable boron or tincontaining reagents, and then coupling with a halogen substitutedcompound Z-X via a palladium catalyzed reaction. Compounds of formula ivare then obtained by reaction with an appropriate sulfamating reagent(for example chlorosulfonamide or see Armitage, I. et. al. U.S. PatentApplication US2009/0036678, and Armitage, I. et. al. Org. Lett., 2012,14 (10), 2626-2629) followed by appropriate deprotection conditions.

A general route for the synthesis of compounds represented by structureix wherein Z is an optionally substituted fused or non-fused aryl orheteroaryl ring and X is a halogen is outlined above in Scheme 2.Cyclization of amino-pyrazole v with a suitable diester and anappropriate base at an elevated temperature is followed by reaction withan appropriate halogenating reagent such as POCl₃ at an elevatedtemperature to give compounds of formula vii. Compounds of formula viiiare then obtained by reaction with an appropriately protectedcyclopentylamine or a salt thereof in the presence of a suitable base.Sulfamation and deprotection following Method 1 as described previouslyprovides compounds of formula ix.

A general route for the synthesis of compounds represented by structurexiii wherein Z is an optionally substituted fused or non-fused aryl orheteroaryl ring and R is an alkyl substituent is outlined above inScheme 3. Cyclization of amino-pyrazole v with an appropriatelysubstituted β-keto ester at an elevated temperature is followed byreaction with an appropriate halogenating reagent such as POCl₃ at anelevated temperature to give compounds of formula xi. Compounds offormula xii are then obtained by reaction with an appropriatelyprotected cyclopentylamine or salt thereof in the presence of a suitablebase. Sulfamation and deprotection following Method 1 as describedpreviously provides compounds of the formula xiii.

Solid State Forms

Provided herein is an assortment of characterizing information, which issufficient, but not all of which is necessary, to describe crystallineForm 1 anhydrous compound I-101((s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate (“Form1”)

FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of Form 1 ofcompound I-101 obtained using CuKα radiation. Peaks identified in FIG. 1include those listed in Table 1.

TABLE 1 Angle 2-Theta ° Intensity % 13.6 32.4 14.8 57.8 15.2 14.2 16.464.8 17.6 20.1 18.0 74.6 19.1 57.0 19.4 24.6 20.5 95.0 20.7 100.0 21.342.7 21.6 23.7 22.4 24.9 23.6 54.7 23.9 24.3 24.6 43.3 27.5 27.4 28.017.1 28.6 18.1 29.3 25.7 31.8 31.6

In some embodiments, Form 1 is characterized by an XRPD pattern having apeak at 2θ angle 20.7°. In some embodiments, Form 1 is characterized byan XRPD pattern having peaks at 2θ angles of 20.5° and 20.7°. In someembodiments, Form 1 is characterized by an XRPD pattern having peaks at2θ angles of 16.4°, 18.0°, 20.5° and 20.7°. In some embodiments, Form 1is characterized by an XRPD pattern having peaks at 2θ angles of 14.8°,16.4°, 18.0°, 19.1°, 20.5°, 20.7° and 23.6°. In some embodiments, Form 1is characterized by an XRPD pattern having peaks at 2θ angles of 13.6°,14.8°, 16.4°, 18.0°, 19.1°, 20.5°, 20.7°, 21.3°, 23.6°, 24.6° and 31.8°.In some embodiments, Form 1 is characterized by an XRPD patternsubstantially as shown in FIG. 1.

In some embodiments, Form 1 is characterized by an XRPD pattern having areference peak with a 2θ angle of 16.4±0.3°, and having peaks at 2θangles of 1.6°, 4.1° and 4.3° relative to the reference peak. The term“reference peak” refers to a peak in the XRPD diffractogram that oneskilled in the art considers as informing the polymorphic form of thematerial, i.e., differentiated from instrument noise. By “relative” itis meant that the observed 2θ angle of each peak will be the sum of the2θ angle of the reference peak and the relative 2θ angle of that peak.For example, if the reference peak has a 2θ angle of 16.3°, the relativepeaks will have 2θ angles of 17.9°, 20.4° and 20.6°; if the referencepeak has a 2θ angle of 16.4°, the relative peaks will have 2θ angles of18.0°, 20.5° and 20.7°; if the reference peak has a 2θ angle of 16.5°,the relative peaks will have 2θ angles of 18.1°, 20.6° and 20.8°; etc.In some embodiments, Form 1 is characterized by an XRPD pattern having areference peak with a 2θ angle of 16.4±0.3°, and having peaks at 2θangles of −1.6°, 1.6°, 2.7°, 4.1°, 4.3° and 7.2° relative to thereference peak. In some embodiments, Form 1 is characterized by an XRPDpattern having a reference peak with a 2θ angle of 16.4±0.3°, and havingpeaks at 2θ angles of −2.8°, −1.6°, 1.6°, 2.7°, 4.1°, 4.3°, 4.9°, 7.2°,8.2° and 15.4° relative to the reference peak. Any of the peaks that oneskilled in the art considers as informing the polymorphic form of thematerial can serve as the reference peak and the relative peaks can thenbe calculated. For example, if the reference peak has a 2θ angle of20.7°, then the relative peaks will have 2θ angles of −4.3°, −2.7° and−0.2° relative to the reference peak.

FIG. 2 shows a differential scanning calorimetry (DSC) profile of Form 1of compound I-101. The DSC thermogram plots the heat flow as a functionof temperature from a sample, the temperature rate change being about10° C./min. In some embodiments, Form 1 is characterized by a DSCprofile substantially as shown in FIG. 2. FIG. 2 shows an exotherm eventwith onset of about 192.3° C. and peak at about 195.3° C.

FIG. 3 shows a thermal gravimetric analysis (TGA) profile of Form 1 ofcompound I-101. The TGA thermogram plots the percent loss of weight ofthe sample as a function of temperature, the temperature rate changebeing about 10° C./min. FIG. 3 shows approximately 0.4% weight loss to120° C. In some embodiments, Form 1 is characterized by a TGA profilesubstantially as shown in FIG. 3. Karl Fischer measurements of Form 1show a water content of about 0.7%.

FIG. 4 shows a raman pattern of Form 1 of compound I-101. In someembodiments, Form 1 is characterized by a raman pattern substantially asshown in FIG. 4. Peaks identified in FIG. 4 in the region of 55 cm⁻¹ to1800 cm⁻¹ include those listed in Table 2 below. FIG. 5A shows a ramanpattern of Form 1 of compound I-101 in the region of 1450 cm⁻¹ to 1520cm⁻¹. In some embodiments, Form 1 is characterized by a peak at 1469.1cm⁻¹. FIG. 6A shows a raman pattern of Form 1 of compound I-101 in theregion of 1100 cm⁻¹ to 1240 cm⁻¹. In some embodiments, Form 1 ischaracterized by a raman pattern substantially as shown in FIG. 6A. Insome embodiments, Form 1 is characterized by a peak at 1200.2 cm⁻¹. FIG.7A shows a raman pattern of Form 1 of compound I-101 in the region ofabout 700 cm⁻¹ to about 1100 cm⁻¹. In some embodiments, Form 1 ischaracterized by a raman pattern substantially as shown in FIG. 7A. Insome embodiments, Form 1 is characterized by peaks at 1059.3, 954.7,845.3 and 805.2 cm⁻¹. In some embodiments, Form 1 is characterized bypeaks at 954.7 and 805.2 cm⁻¹.

TABLE 2 Peak (cm⁻¹) Intensity 62.7 1057.18 93.4 1047.64 109.8 1069.98193.2 340.36 226.8 158.25 266.3 26.10 283.1 65.41 308.3 51.53 353.171.31 425.3 61.00 469.9 65.13 545.2 64.03 595.1 45.09 639.9 188.46 707.5166.50 752.4 105.67 771.8 92.90 805.2 466.55 845.3 113.29 954.7 466.61986.8 70.99 997.9 775.23 1059.3 66.37 1075.1 34.74 1101.2 38.50 1166.976.42 1200.2 218.72 1302.3 295.74 1345.0 886.09 1440.9 957.45 1469.1116.07 1503.7 1098.73 1541.6 98.76 1601.4 2315.65

In some embodiments, Form 1 of compound I-101 is characterized by atleast one of the following features (I-i)-(I-iv):

-   -   (I-i) an XRPD pattern having peaks at 2θ angles of 16.4°, 18.0°,        20.5°, and 20.7° as shown in FIG. 1;    -   (I-ii) a DSC profile substantially as shown in FIG. 2;    -   (I-iii) a TGA profile substantially as shown in FIG. 3.    -   (I-iv) a raman pattern substantially as shown in FIG. 4.

In some embodiments, Form 1 is characterized by at least two of thefeatures (I-i)-(I-iv). In some embodiments, Form 1 is characterized byat least three of the features (I-i)-(I-iv). In some embodiments, Form 1is characterized by all four of the features (I-i)-(I-iv).

Provided herein is an assortment of characterizing information, which issufficient, but not all of which is necessary, to describe crystallineForm 2 monohydrated compound I-101((s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate (“Form 2”).

FIG. 8 shows an X-ray powder diffraction (XRPD) pattern of crystallineForm 2 monohydrated compound I-101 obtained using CuKα radiation. Peaksidentified in FIG. 8 include those listed in Table 3.

TABLE 3 Angle 2-Theta ° Intensity % 6.7 100 11.5 61.6 12.0 18.7 13.324.4 13.7 10.1 14.5 24.8 14.8 15.0 15.2 44.3 16.3 24.8 16.6 42.2 17.669.6 18.2 32.6 18.5 29.5 19.1 55.5 19.4 19.9 20.0 80.3 20.3 48.7 20.828.6 21.2 15.7 21.6 73.8 21.8 37.2 22.6 19.7 23.1 56.7 23.3 59.7 24.018.7 24.6 10.8 25.2 24.1 25.4 41.9 26.1 21.5 26.8 31.4 27.4 15.9 27.816.4 28.6 24.8 29.2 11.5 29.6 11.5 30.4 11.2 30.8 16.2 31.5 16.6 33.116.2 34.4 16.2 35.6 12.6 37.1 15.5 37.6 20.4

In some embodiments, Form 2 is characterized by an XRPD pattern havingpeaks at 2θ angles of 6.7°, 17.6°, 20.0° and 21.6°. In some embodiments,Form 2 is characterized by an XRPD pattern having peaks at 2θ angles of6.7°, 11.5°, 17.6°, 19.1°, 20.0°, 21.6°, 23.1° and 23.3°. In someembodiments, Form 2 is characterized by an XRPD pattern having peaks at2θ angles of 6.7°, 11.5°, 15.2°, 16.6°, 17.6°, 19.1°, 20.0°, 20.3°,21.6°, 23.1°, 23.3° and 25.4°. In some embodiments, Form 2 ischaracterized by an XRPD pattern substantially as shown in FIG. 8.

In some embodiments, Form 2 is characterized by an XRPD pattern having areference peak with a 2θ angle of 6.7±0.3°, and having peaks at 2θangles of 10.9°, 13.3° and 14.9° relative to the reference peak. Theterms “reference peak” and “relative” have the same meaning aspreviously described. In some embodiments, Form 2 is characterized by anXRPD pattern having a reference peak with a 2θ angle of 6.7±0.3°, andhaving peaks at 2θ angles of 4.8°, 10.9°, 12.4°, 13.3°, 14.9°, 16.4° and16.6°, relative to the reference peak. In some embodiments, Form 2 ischaracterized by an XRPD pattern having a reference peak with a 2θ angleof 2θ angle of 6.7±0.3°, and having peaks at 2θ angles of 4.8°, 8.5°,9.9°, 10.9°, 12.4°, 13.3°, 13.6°, 14.9°, 16.4°, 16.6° and 18.7°,relative to the reference peak. Any of the peaks that one skilled in theart considers as informing the polymorphic form of the material canserve as the reference peak and the relative peaks can then becalculated. For example, if the reference peak has a 2θ angle of 20.0°,then the relative peaks will have 2θ angles of −13.3°, −2.4° and 1.6°relative to the reference peak.

FIG. 9 shows a differential scanning calorimetry (DSC) profile of Form 2of compound I-101. The DSC thermogram plots the heat flow as a functionof temperature from a sample, the temperature rate change being about10° C./min. In some embodiments, Form 2 is characterized by a DSCprofile substantially as shown in FIG. 9. FIG. 9 shows an endothem withonset of about 81.2° C. and a peak at about 108.3° C. corresponding to aloss of water followed by an exotherm with an onset of about 151.1° C.and peak at about 153.2° C.

FIG. 10 shows a thermal gravimetric analysis (TGA) profile of Form 2 ofcompound I-101. The TGA thermogram plots the percent loss of weight ofthe sample as a function of temperature, the temperature rate changebeing about 10° C./min. FIG. 10 shows approximately 3.1% weight loss(w/w) to 120° C. suggesting that Form 2 is a monohydrate. In someembodiments, Form 2 of compound I-101 is characterized by a TGA profilesubstantially as shown in FIG. 10. Karl Fischer measurements of Form 2of compound I-101 show a water content of about 2.9% further confirmingthat Form 2 is a monohydrate.

FIG. 11 shows a raman pattern of Form 2 of compound I-101. In someembodiments, Form 2 is characterized by a raman pattern substantially asshown in FIG. 11. Peaks identified in FIG. 11 in the region of 55 cm⁻¹to 1800 cm⁻¹ include those listed in Table 4 below. FIG. 5B shows araman pattern of Form 2 of compound I-101 in the region of 1450 cm⁻¹ to1520 cm⁻¹. FIG. 6B shows a raman pattern of Form 2 of compound I-101 inthe region of 1100 cm⁻¹ to 1240 cm⁻¹. In some embodiments, Form 1 ischaracterized by a raman pattern substantially as shown in FIG. 6B. Insome embodiments, Form 1 is characterized by a peak at 1205.4 cm⁻¹. FIG.7B shows a raman pattern of Form 2 of compound I-101 in the region ofabout 700 cm⁻¹ to about 1100 cm⁻¹. In some embodiments, Form 2 ischaracterized by a raman pattern substantially as shown in FIG. 7B. Insome embodiments, Form 2 is characterized by peaks at 958.7 and 923.2cm⁻¹.

TABLE 4 Peak (cm⁻¹) Intensity 60 839.324 94.7 813.247 190.4 123.76 216.861.08 285.5 35.40 353.7 27.34 424.4 21.79 470.9 28.93 545.7 28.08 640.597.91 707.4 59.11 753.4 51.10 773.9 35.84 809.9 163.67 923.2 26.66 958.7175.20 997.9 281.45 1068.5 22.13 1167.8 26.59 1205.4 79.16 1302.2 147.411343.7 278.22 1442.1 309.65 1504.6 325.60 1542.4 39.61 1571.0 34.151599.3 768.82

In some embodiments, Form 2 of compound I-101 is characterized by atleast one of the following features (I-v)-(I-viii):

-   -   (I-v) an XRPD pattern having peaks at 2θ angles of 6.7°, 17.6°,        20.0° and 21.6° as shown in FIG. 8;    -   (I-vi) a DSC profile substantially as shown in FIG. 9;    -   (I-vii) a TGA profile substantially as shown in FIG. 10.    -   (I-viii) a raman pattern substantially as shown in FIG. 11.

In some embodiments, Form 2 is characterized by at least two of thefeatures (I-v)-(I-viii). In some embodiments, Form 2 is characterized byat least three of the features (I-v)-(I-viii). In some embodiments, Form2 is characterized by all four of the features (I-v)-(I-viii).

The chemical entities of this invention are useful inhibitors of UAEactivity. Inhibitors are meant to include chemical entities which reducethe promoting effects of UAE initiated conjugation of ubiquitin totarget proteins (e.g., reduction of ubiquitination), reduceintracellular signaling mediated by ubiquitin conjugation, and/or reduceproteolysis mediated by ubiquitin conjugation (e.g., inhibition ofcellular ubiquitin conjugation, ubiquitin dependent signaling andubiquitin dependent proteolysis (e.g., the ubiquitin-proteasomepathway)). Thus, the chemical entities of this invention may be assayedfor their ability to inhibit UAE in vitro or in vivo, or in cells oranimal models according to methods provided in further detail herein, ormethods known in the art. The chemical entities may be assessed fortheir ability to bind or modulate UAE activity directly. Alternatively,the activity of the chemical entities may be assessed through indirectcellular assays, or assays measuring downstream effects of UAE promotedubiquitin activation to assess inhibition of downstream effects of UAEinhibition (e.g., inhibition of ubiquitin dependent proteolysis). Forexample, activity may be assessed by detection of ubiquitin conjugatedsubstrates (e.g., ubiquitin charged E2s or ubiquitinated substrates);detection of downstream protein substrate stabilization (e.g.,stabilization of c-myc, stabilization of IκB); detection of inhibitionof UPP activity; detection of downstream effects of UAE inhibition andsubstrate stabilization (e.g., reporter assays, e.g., NFκB reporterassays, p27 reporter or loss of cellular polyubiquitin assays). Assaysfor assessing activities are described below in the Examples sectionand/or are known in the art.

Derivatives

It will be appreciated that the chemical entities of this invention maybe derivatized at functional groups to provide prodrug derivatives whichare capable of conversion back to the parent chemical entities in vivo.Examples of such prodrugs include the physiologically acceptable andmetabolically labile derivatives. More specifically, the prodrug of thechemical entity of this invention is a carbamate or amide of the —NH—group of the chemical entity, or an ether or ester of the —OH group ofthe chemical entity.

Such carbamate prodrugs of the —NH— group of the chemical entity includethe following carbamates: 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl, 17-tetrabenzo[a,c,g,i]fluorenylmethyl,2-chloro-3-indenylmethyl, benz[f]inden-3-ylmethyl,2,7,di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,1,1-dioxobenzo[b]thiophene-2-yl-methyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,2-chloroethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-tert-butylphenyl)-1-methylethyl, 2-(2′-and 4′-pyridyl)ethyl,2,2-bis(4′-nitrophenyl)ethyl, N-2-pivaloylamino)-1,1-dimethylethyl,2-[(2-nitrophenyl)dithio]-1-phenylethyl,2-(N,N-dicyclohexylcarboxamideo)ethyl, tert-butyl, 1-adamantyl,2-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl,3-(3′-pyridyl)prop-2-enyl, 8-quinolyl, N-hydroxypiperidinyl,alkyldithio, benzyl, para-methoxybenzyl, para-nitrobenzyl,para-bromobenzyl, para-chlorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl,phenothiazinyl-(10)-carbonyl, N′-para-toluenesulfonylaminocarbonyl andN′-phenylaminothiocarbonyl.

Such amide prodrugs of the —NH— group of the chemical entity include thefollowing amides: N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-4-pentenoyl,N-picolinoyl, N-3-pyridylcarboxamido, N-benzoylphenylalanyl, N-benzoyland N-para-phenylbenzoyl.

Such ether prodrugs of the —OH group of the chemical entity include thefollowing ethers: methyl, methoxymethyl, methylthiomethyl,(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,para-methoxybenzyloxymethyl, para-nitrobenzyloxymethyl,ortho-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,tert-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,menthoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8,-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl,1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,1-methyl-1-phenoxyethyl, 2,2,2,-trichloroethyl,1,1-dianisyl-2,2,2,-trichloroethyl,1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl,2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tert-butyl, allyl,propargyl, para-chlorophenyl, para-methoxyphenyl, para-nitrophenyl,2,4-dinitrophenyl, 2,3,5,6-tetrafluoro-4-trifluoromethyl)phenyl, benzyl,para-methoxybenzyl, 3,4-dimethoxybenzyl, ortho-nitrobenzyl,para-nitrobenzyl, para-halobenzyl, 2,6-dichlorobenzyl, para-cyanobenzyl,para-phenylbenzyl, 2,6-difluorobenzyl, para-acylaminobenzyl,para-azidobenzyl, 4-azido-3-chlorobenzyl, 2-trifluoromethylbenzyl,para-(methylsulfinyl)benzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolylN-oxido, 2-quinolinylmethyl, 1-pyrenylmethyl, diphenylmethyl,p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,alpha-naphthyldiphenylmethyl, para-methoxyphenyldiphenylmethyl,di(para-methoxyphenyl)phenylmethyl, tri(para-methoxyphenyl)methyl,4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tri(levulinoyloxyphenyl)methyl,4,4′,4″-tri(benzoyloxyphenyl)methyl,4,4′-dimethoxy-3″-[N-(imidazolylmethyl)trityl,4,4′-dimethoxy-3″[N-imidazolylethyl]carbamoyl]trityl,1.1-bis(4-methoxyphenyl)-1′-pyrenylmethyl,4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4″-dimethoxytrityl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl,triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,diethylisopropylsilyl, dimethylthexylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, tribenzylsilyl, tri-para-xylylsilyl,triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl,tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl,(2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl andtert-butoxydiphenylsilyl.

Such ester prodrugs of the —OH group of the chemical entity include thefollowing esters: formate, benzoylformate, acetate, chloroacetate,dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, para-chlorophenoxyacetate,phenylacetate, para-P-phenylacetate, diphenylacetate, nicotinate,3-phenylpropionate, 4-pentenoate, 4-oxopentanoate,4,4-(ethylenedithio)pentanoate,5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy]levulinate, pivaloate,1-adamantoate, crotonate, 4-methoxycrotonate, benzoate,para-phenylbenzoate and 2,4,6-trimethylbenzoate. Additionally, anyphysiologically acceptable equivalents of the present chemical entities,similar to the metabolically labile ether, esters of the —OH group, orcarbamates or amides of the —NH— group, which are capable of producingthe parent chemical entities described herein in vivo, are within thescope of this invention. See e.g., Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed. John Wiley & Sons, Inc. (1999).

Compositions

Some embodiments of this invention relate to a composition comprising achemical entity of this invention and a pharmaceutically acceptablecarrier. Some embodiments of this invention relate to a compositioncomprising a prodrug of a chemical entity of this invention and apharmaceutically acceptable carrier.

If a pharmaceutically acceptable salt is the chemical entity of theinvention utilized in these compositions, the salts preferably arederived from inorganic or organic acids and bases. For reviews ofsuitable salts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19 (1977)and Remington: The Science and Practice of Pharmacy, 20th Ed., A.Gennaro (ed.), Lippincott Williams & Wilkins (2000) (“Remington's”).

Examples of suitable acid addition salts include the following: acetate,adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate,butyrate, citrate, camphorate, camphor sulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Examples of suitable base addition salts include ammonium salts, alkalimetal salts, such as sodium and potassium salts, alkaline earth metalsalts, such as calcium and magnesium salts, salts with organic bases,such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts withamino acids such as arginine, lysine, and so forth.

Also, basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The pharmaceutical compositions of the invention preferably are in aform suitable for administration to a recipient subject, preferably amammal, more preferably a human. The term “pharmaceutically acceptablecarrier” is used herein to refer to a material that is compatible withthe recipient subject, and is suitable for delivering an active agent tothe target site without terminating the activity of the agent. Thetoxicity or adverse effects, if any, associated with the carrierpreferably are commensurate with a reasonable risk/benefit ratio for theintended use of the active agent. Many such pharmaceutically acceptablecarriers are known in the art. See, e.g., Remington's; Handbook ofPharmaceutical Excipients, 6th Ed., R. C. Rowe et al. (eds.),Pharmaceutical Press (2009).

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes, amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. Formulations may optionally containstabilizers, pH modifiers, surfactants, solubilizing agents,bioavailability modifiers and combinations of these.

Pharmaceutically acceptable carriers that may be used in thesecompositions include ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates or carbonates, glycine, sorbic acid, potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the present inventionmay be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir. The term “parenteral” as used herein includes subcutaneous,intravenous, intraperitoneal, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques. Preferably, thecompositions are administered orally, intravenously, or subcutaneously.The formulations of the invention may be designed to be short-acting,fast-releasing, or long-acting. Still further, compounds can beadministered in a local rather than systemic means, such asadministration (e.g., by injection) at a tumor site.

Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a liquid, such as an oil, water, an alcohol, andcombinations of these. Solubilizing agents such as cyclodextrins may beincluded. Pharmaceutically suitable surfactants, suspending agents, oremulsifying agents, may be added for oral or parenteral administration.Suspensions may include oils, such as peanut oil, sesame oil, cottonseedoil, corn oil and olive oil. Suspension preparation may also containesters of fatty acids such as ethyl oleate, isopropyl myristate, fattyacid glycerides and acetylated fatty acid glycerides. Suspensionformulations may include alcohols, such as ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such aspoly(ethyleneglycol), petroleum hydrocarbons such as mineral oil andpetrolatum; and water may also be used in suspension formulations.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation. Compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmulti-dose containers.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including capsules,tablets, aqueous suspensions or solutions. When aqueous suspensions arerequired for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added. In such solid dosageforms, the active chemical entity is mixed with at least one inert,pharmaceutically acceptable excipient or carrier such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol, micro-crystalline cellulose andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, sucrose, and acacia, c) humectants such as glycerol,d) disintegrating agents such as agar-agar, calcium carbonate,polyvinylpyrrolidinone, croscarmellose, sodium starch glycolate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate, e) solution retarding agents such as paraffin, f) absorptionaccelerators such as quaternary ammonium compounds, g) wetting agentssuch as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and i) lubricants such astalc, calcium stearate, magnesium stearate, sodium stearyl fumarate,solid polyethylene glycols, sodium lauryl sulfate, silicon dioxide andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

The active chemical entity can also be in micro-encapsulated form withone or more excipients as noted above. The solid dosage forms oftablets, dragees, capsules, pills, and granules can be prepared withcoatings and shells such as enteric coatings, release controllingcoatings and other coatings well known in the pharmaceutical formulatingart. In such solid dosage forms the active compound may be admixed withat least one inert diluent such as sucrose, lactose or starch. Suchdosage forms may also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g., tableting lubricants andother tableting aids such a magnesium stearate and microcrystallinecellulose. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents. They may optionally containopacifying agents and can also be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions that can be used include polymeric substances and waxes.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These may be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used. For topicalapplications, the pharmaceutical compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this invention include mineral oil, liquid petrolatum,white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, the pharmaceuticalcompositions may be formulated in a suitable lotion or cream containingthe active components suspended or dissolved in one or morepharmaceutically acceptable carriers. Suitable carriers include mineraloil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The pharmaceutical compositions of this invention are particularlyuseful in therapeutic applications relating to disorders as describedherein (e.g., proliferation disorders, e.g., cancers, inflammatory,neurodegenerative disorders). The term “subject” as used herein, meansan animal, preferably a mammal, more preferably a human. The term“patient” as used herein, means a human. Preferably, the composition isformulated for administration to a patient or subject having or at riskof developing or experiencing a recurrence of the relevant disorderbeing treated. Preferred pharmaceutical compositions of the inventionare those formulated for oral, intravenous, or subcutaneousadministration. However, any of the above dosage forms containing atherapeutically effective amount of a chemical entity of the inventionare well within the bounds of routine experimentation and therefore,well within the scope of the instant invention. In certain embodiments,the pharmaceutical composition of the invention may further compriseanother therapeutic agent. Preferably, such other therapeutic agent isone normally administered to patients with the disorder, disease orcondition being treated.

By “therapeutically effective amount” is meant an amount of the chemicalentity or composition sufficient, upon single or multiple doseadministration, to cause a detectable decrease in UAE activity and/orthe severity of the disorder or disease state being treated.“Therapeutically effective amount” is also intended to include an amountsufficient to treat a cell, prolong or prevent advancement of thedisorder or disease state being treated (e.g., prevent additional tumorgrowth of a cancer, prevent additional inflammatory response),ameliorate, alleviate, relieve, or improve a subject's symptoms of the adisorder beyond that expected in the absence of such treatment. Theamount of UAE inhibitor required will depend on the particular compoundof the composition given, the type of disorder being treated, the routeof administration, and the length of time required to treat thedisorder. It should also be understood that a specific dosage andtreatment regimen for any particular patient will depend upon a varietyof factors, including the activity of the specific chemical entityemployed, the age, body weight, general health, sex, and diet of thepatient, time of administration, rate of excretion, drug combinations,the judgment of the treating physician, and the severity of theparticular disease being treated. In certain aspects where the inhibitoris administered in combination with another agent, the amount ofadditional therapeutic agent present in a composition of this inventiontypically will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably, the amount of additional therapeuticagent will range from about 50% to about 100% of the amount normallypresent in a composition comprising that agent as the onlytherapeutically active agent.

Uses

In some embodiments, the invention relates to a method of inhibiting ordecreasing UAE activity in a sample comprising contacting the samplewith a chemical entity of this invention, or composition comprising achemical entity of the invention. The sample, as used herein, includessample comprising purified or partially purified UAE, cultured cells orextracts of cell cultures; biopsied cells or fluid obtained from amammal, or extracts thereof; and body fluid (e.g., blood, serum, saliva,urine, feces, semen, tears) or extracts thereof. Inhibition of UAEactivity in a sample may be carried out in vitro or in vivo, in cellulo,or in situ.

In some embodiments, the invention provides a method for treating apatient having a disorder, a symptom of a disorder, at risk ofdeveloping, or experiencing a recurrence of a disorder, comprisingadministering to the patient a chemical entity or pharmaceuticalcomposition according to the invention. Treating can be to cure, heal,alleviate, relieve, alter, remedy, ameliorate, palliate, improve oraffect the disorder, the symptoms of the disorder or the predispositiontoward the disorder. While not wishing to be bound by theory, treatingis believed to cause the inhibition of growth, ablation, or killing of acell or tissue in vitro or in vivo, or otherwise reduce capacity of acell or tissue (e.g., an aberrant cell, a diseased tissue) to mediate adisorder, e.g., a disorder as described herein (e.g., a proliferativedisorder, e.g., a cancer, inflammatory disorder). As used herein,“inhibiting the growth” or “inhibition of growth” of a cell or tissue(e.g., a proliferative cell, tumor tissue) refers to slowing,interrupting, arresting or stopping its growth and metastases and doesnot necessarily indicate a total elimination of growth.

UAE represents a novel protein homeostasis target opportunity for thetreatment of cancer and other human diseases where ubiquitin biology ispresent. Disease applications include those disorders in whichinhibition of UAE activity is detrimental to survival and/or expansionof diseased cells or tissue (e.g., cells are sensitive to UAEinhibition; inhibition of UAE activity disrupts disease mechanisms;reduction of UAE activity stabilizes protein which are inhibitors ofdisease mechanisms; reduction of UAE activity results in inhibition ofproteins which are activators of disease mechanisms). Diseaseapplications are also intended to include any disorder, disease orcondition which requires effective ubiquitination activity, whichactivity can be regulated by diminishing UAE activity.

For example, methods of the invention are useful in treatment ofdisorders involving cellular proliferation, including disorders whichrequire effective ubiquitin ligase dependent ubiquitination andsignaling or proteolysis (e.g., the ubiquitin proteasome pathway) formaintenance and/or progression of the disease state. The methods of theinvention are useful in treatment of disorders mediated via proteins(e.g., NFκB activation, p27^(Kip) activation, p21^(WAF/CIP1) activation,p53 activation) which are regulated by UAE activity. Relevant disordersinclude proliferative disorders, most notably cancers and inflammatorydisorders (e.g., rheumatoid arthritis, inflammatory bowel disease,asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis,dermatosis (e.g., atopic dermatitis, psoriasis), vascular proliferativedisorders (e.g., atherosclerosis, restenosis) autoimmune diseases (e.g.,multiple sclerosis, tissue and organ rejection)); as well asinflammation associated with infection (e.g., immune responses),neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson'sdisease, motor neuron disease, neuropathic pain, triplet repeatdisorders, astrocytoma, and neurodegeneration as result of alcoholicliver disease), ischemic injury (e.g., stroke), and cachexia (e.g.,accelerated muscle protein breakdown that accompanies variousphysiological and pathological states, (e.g., nerve injury, fasting,fever, acidosis, HIV infection, cancer affliction, and certainendocrinopathies).

The compounds and pharmaceutical compositions of the invention areparticularly useful for the treatment of cancer. As used herein, theterm “cancer” refers to a cellular disorder characterized byuncontrolled or disregulated cell proliferation, decreased cellulardifferentiation, inappropriate ability to invade surrounding tissue,and/or ability to establish new growth at ectopic sites. The term“cancer” includes solid tumors and bloodborne tumors. The term “cancer”encompasses diseases of skin, tissues, organs, bone, cartilage, blood,and vessels. The term “cancer” further encompasses primary andmetastatic cancers.

In some embodiments, the cancer is a solid tumor. Examples of solidtumors that can be treated by the methods of the invention includepancreatic cancer; bladder cancer; colorectal cancer; rectal cancer,breast cancer, including metastatic breast cancer; prostate cancer,including androgen-dependent and androgen-independent prostate cancer;renal cancer, including, e.g., metastatic renal cell carcinoma;hepatocellular cancer; bronchus and lung cancer, including, e.g.,non-small cell lung cancer (NSCLC), squamous lung cancer, small celllung cancer (SCLC), bronchioloalveolar carcinoma (BAC), andadenocarcinoma of the lung; ovarian cancer, including, e.g., progressiveepithelial or primary peritoneal cancer; cervical cancer; endometrialcancer, bladder cancer, gastric cancer; esophageal cancer; head and neckcancer, including, e.g., squamous cell carcinoma of the head and neck,nasopharyngeal, oral cavity and pharynxthyroid cancer, melanoma;neuroendocrine cancer, including metastatic neuroendocrine tumors; braintumors, including, e.g., glioma, anaplastic oligodendroglioma, adultglioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer;and soft tissue sarcoma.

In some embodiments, the cancer is a hematologic malignancy. Examples ofhematologic malignancy include acute myeloid leukemia (AML); chronicmyelogenous leukemia (CML), including accelerated CML and CML blastphase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocyticleukemia (CLL); lymphomas including: Hodgkin's disease (HD);non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantlecell lymphoma; B-cell lymphoma; diffuse large B-Cell lymphoma (DLBCL),and T-cell lymphoma; multiple myeloma (MM); amyloidosis; Waldenstrom'smacroglobulinemia; myelodysplastic syndromes (MDS), including refractoryanemia (RA), refractory anemia with ringed siderblasts (RARS),(refractory anemia with excess blasts (RAEB), and RAEB in transformation(RAEB-T); and myeloproliferative syndromes.

In some embodiments, the cancer is lung cancer, ovarian cancer, coloncancer, or breast cancer. In some embodiments, the cancer is acutemyeloid leukemia. In some embodiments the cancer is lymphoma.

Depending on the particular disorder or condition to be treated, in someembodiments, the UAE inhibitor of the invention is administered inconjunction with additional therapeutic agent or agents. In someembodiments, the additional therapeutic agent(s) is one that is normallyadministered to patients with the disorder or condition being treated.As used herein, additional therapeutic agents that are normallyadministered to treat a particular disorder or condition are known as“appropriate for the disorder or condition being treated.”

The UAE inhibitor of the invention may be administered with the othertherapeutic agent in a single dosage form or as a separate dosage form.When administered as a separate dosage form, the other therapeutic agentmay be administered prior to, at the same time as, or followingadministration of the UAE inhibitor of the invention.

In some embodiments, the UAE enzyme inhibitor of the invention isadministered in conjunction with a therapeutic agent selected fromcytotoxic agents, radiotherapy, and immunotherapy appropriate fortreatment of proliferative disorders and cancer. Examples of cytotoxicagents suitable for use in combination with the UAE inhibitors of theinvention include: antimetabolites, including, e.g., capecitibine,gemcitabine, 5-fluorouracil or 5-fluorouracil/leucovorin, fludarabine,cytarabine, mercaptopurine, thioguanine, pentostatin, and methotrexate;topoisomerase inhibitors, including, e.g., etoposide, teniposide,camptothecin, topotecan, irinotecan, doxorubicin, and daunorubicin;vinca alkaloids, including, e.g., vincristine and vinblastin; taxanes,including, e.g., paclitaxel and docetaxel; platinum agents, including,e.g., cisplatin, carboplatin, and oxaliplatin; antibiotics, including,e.g., actinomycin D, bleomycin, mitomycin C, adriamycin, daunorubicin,idarubicin, doxorubicin and pegylated liposomal doxorubicin; alkylatingagents such as melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine, andcyclophosphamide; including, e.g., CC-5013 and CC-4047; protein tyrosinekinase inhibitors, including, e.g., imatinib mesylate and gefitinib;proteasome inhibitors, including, e.g., bortezomib; thalidomide andrelated analogs; antibodies, including, e.g., trastuzumab, rituximab,cetuximab, and bevacizumab; mitoxantrone; dexamethasone; prednisone; andtemozolomide.

Other examples of agents the inhibitors of the invention may be combinedwith include anti-inflammatory agents such as corticosteroids, TNFblockers, II-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporine,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophosphamide, azathioprine, methotrexate, andsulfasalazine; antibacterial and antiviral agents; and agents forAlzheimer's treatment such as donepezil, galantamine, memantine andrivastigmine.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examples are forthe purpose of illustration only and are not intended to be construed aslimiting the scope of the invention in any way.

Examples Abbreviations and Nomenclature

Compounds which were synthesized as racemic mixtures are specified as“(rac)-” in the corresponding name. R/S stereochemical assignments havebeen used to define the relative stereochemistry of molecules. It isunderstood that unless specifically indicated, compounds are racemicmixtures containing the compound with the designated stereochemistryalong with its enantiomer. Compounds which were synthesized as singleenantiomers are specified as “(s.e.)” in the corresponding name.

AA ammonium acetate

ACN acetonitrile

d doublet

dd doublet of doublets

DMF N, N-dimethylformamide

DMSO dimethylsulfoxide

EtOAc ethyl acetate

FA formic acid

J coupling constant

hr hours

Hz hertz

LAH lithium aluminum hydride

LCMS liquid chromatography mass spectrum

LDA lithium diisopropylamide

m multiplet

MeOH methanol

s singlet

t triplet

THF tetrahydrofuran

q quartet

Analytical Methods

LCMS data were obtained either (i) using an Agilant 1100 LC (column:Waters Symmetry, 3.5 μm C18 100×4.6 mm) and a Waters ZQ MS using thefollowing gradients:

-   -   Method Formic Acid (FA): Composition of Mobile Phase A: 99%        H₂O+1% ACN [+0.1% formic acid]; Composition of Mobile Phase B:        95% ACN+5% H₂O [+0.1% formic acid]. Linear Gradient: 5-100% B,        10 minute run at 1 mL/minute.    -   Method Ammonium Acetate (AA): Composition of Mobile Phase A: 99%        H₂O+1% ACN [+10 mM ammonium acetate]; Composition of Mobile        Phase B: 95% ACN+5% H₂O [+10 mM ammonium acetate]. Linear        Gradient: 5-100% B, 10 minute run at 1 mL/minute;        or (ii) using an Agilant 1100 LC (column: Luna C18(2) 100A,        150×4.60 mm, 5 micron) and a Agilant 1100 LC/MS using the        following gradient:    -   Method Formic Acid 2 (FA2): Composition of Mobile Phase A: 99%        H₂O+1% ACN [+0.1% formic acid]; Composition of Mobile Phase B:        95% ACN+5% H₂O [+0.1% formic acid]. Linear Gradient: 5-100% B,        20 minute run at 1 mL/minute.

Preparative HPLC is performed using a Phenominex Luna C18 column.

NMR spectrum is shown by proton NMR, using a 300 MHz Bruker Avancespectrometer equipped with a 5 mm QNP probe and a 400 MHz Bruker AvanceII spectrometer equipped with a 5 mm QNP probe for the measurement; δvalues are expressed in ppm.

X-ray Powder Diffraction. XRPD is performed using a Bruker AXS D8Advance X-ray Diffractometer using CuKα radiation (40 kV, 40 mA), θ−2 θgoniometer, and divergence of V4 and receiving slits, a Ge monochormatorand a Lynxeye detector. Samples are run under ambient conditions as flatplate specimens using powder. The sample is gently packed into a cavitycut into polished, zero-background (510) silicon wafer. The sample isrotated in its own plane during analysis. The data are collected on anangular range of 2 to 42 °2θ, with a step size of 0.05 °2θ and acollection time of 0.5 s/step. All data collection is performed usingDiffrac Plus XRD Commander v2.6.1 software. Data analysis andpresentation is performed using Diffrac Plus EVA v13.0.0.2 or v15.0.0.0software.

Raman spectrum is collected using a ThermoScientific DXR RamanMicroscope with the following parameters: laser 780 nm; laser powerlevel 20.0 mW; filter 780 nm; grating 400 lines/nm; spectrographaperture 50 μm pinhole; exposure time 30 secs; and number of exposures2. The range of raman shift was 55.13 to 3411.62 cm⁻¹. Instrumentcontrol and data analysis software is OMNIC 8.3.

Thermal Analysis. The thermal events are analyzed using differentialscanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSCdata is collected on a Mettler DSC 823E. Typically, 0.5-5.0 mg of samplein a pin-holed aluminium pan is heated at 10° C./min from 25° C. to 300°C. A nitrogen sample purge is maintained at 50 mL/min over the sample.Instrument control and data analysis software is STARe v9.20. TGA datais collected on a Mettler TGA/SDTA 851e. Typically, 5-30 mg of sample isloaded onto a pre-weighed aluminium crucible and was heated at 10°C./min from ambient temperature to 350° C. A nitrogen sample purge ismaintained at 50 mL/min over the sample. Instrument control and dataanalysis software is STARe v9.20.

Synthetic Methods Example 1a. Synthesis of(s.e.)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol

Step 1:(s.e.)-(1R,2S,3R,4R)-1-Amino-2,3-(isoproplydenyl)dihydroxy-4-hydroxymethylcyclopentane

To a mixture of(s.e.)-(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diolhydrochloride (7.00 g, 38.1 mmol; obtained as a single enantiomer by themethod described in WO2008/019124) and p-toluenesulfonic acidmonohydrate (8.23 g, 43.3 mmol) in methanol (43 mL) is added2,2-dimethoxypropane (32.3 mL, 263 mmol). The mixture is stirred at roomtemperature overnight and then neutralized with 7 M NH₃/MeOH andconcentrated to dryness. The residue is taken up in 2M K₂CO₃ (50 ml) andextracted with EtOAc/CH₂CH₂ 1:1 (3×50 ml). The combined organics aredried over Na₂SO₄, filtered, and concentrated in vacuo to give(s.e.)-(1R,2S,3R,4R)-1-amino-2,3-(isoproplydenyl)dihydroxy-4-hydroxymethylcyclopentane (6.8 g, yield 95%). ¹H NMR (400 MHz, DMSO) δ 4.49-4.40 (m,1H), 4.16-4.05 (m, 1H), 3.44-3.37 (m, 2H), 3.25-3.16 (m, 1H), 2.52-2.42(m, 1H), 2.16-2.04 (m, 2H), 1.32 (s, 3H), 1.18 (s, 3H).

Step 2:(s.e.)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol

To a suspension of(1R,2S,3R,4R)-1-amino-2,3-(isoproplydenyl)dihydroxy-4-hydroxymethylcyclopentane (2.76 g, 14.7 mmol) in ethanol (46.5 mL) is addedtriethylamine (4.28 mL, 30.7 mmol) and2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (3.58 g, 15.4 mmol; obtainedby the method described in J. Med. Chem. 2010, 53, 1238-1249). Thereaction mixture is heated at 100° C. for 3.5 hr and then cooled to roomtemperature and concentrated to dryness. The residue is dissolved inchloroform and then washed with saturated sodium bicarbonate and brine.The organic layer is dried over Na₂SO₄, filtered and concentrated invacuo. The solid is triturated with diethyl ether and filtered toprovide(s.e.)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(5.0 g, yield 88%). LCMS: (AA) M+383; ¹H NMR (400 MHz, MeOD) δ 8.14 (d,J=5.6 Hz, 1H), 6.43 (s, 1H), 6.28 (d, J=5.7 Hz, 1H), 4.64-4.56 (m, 1H),4.55-4.48 (m, 1H), 4.15-4.05 (m, 1H), 3.75-3.61 (m, 2H), 2.63-2.53 (m,1H), 2.41-2.31 (m, 1H), 1.88-1.78 (m, 1H), 1.51 (s, 3H), 1.30 (s, 3H).

Example 1b. Synthesis of(rac)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol

The method used to synthesize(s.e.)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanolas a single enantiomer is followed to generate(rac)-rel-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanolstarting from(rac)-rel-(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diolhydrochloride.

Method A [Example 2]

The following procedure describes the synthesis of enantiomerically purecompounds starting from(s.e.)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol.The same procedure is used to synthesize racemic compounds starting from(rac)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol.

Example 2a. Synthesis of(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylsulfamate (I-98)

Step 1:(s.e)-((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

A microwave vial is charged with{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(1.50 g, 3.91 mmol), 1-naphthaleneboronic acid (1.01 g, 5.87 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.160 g, 0.196 mmol), cesium carbonate (2.55g, 7.83 mmol) and dioxane/water (6:1, 25 mL). The reaction mixture isheated in the microwave at 120° C. for 90 minutes and then cooled toroom temperature and concentrated in vacuo. The crude material ispurified by column chromatography (eluent: ethyl acetate/hexane) toprovide(s.e)-((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(1.5 g, yield 89%). LCMS: (AA) M+1 431.

Step 2:(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylsulfamate (I-98)

To a vial charged with(s.e.)-((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(1.76 g, 4.09 mmol) in N,N-dimethylformamide (7.20 mL) is addedchlorosulfonamide (1.42 g, 12.3 mmol; obtained by the method describedin J. Am. Chem. Soc. 2005, 127, 15391). After 1 hr, the reaction isquenched with methanol (5 mL). 6.0 M hydrochloric acid in water (3.41mL, 20.4 mmol) is added and the mixture is stirred for 1 hr. Solvent isremoved in vacuo and the crude material is purified by preparative HPLCto provide(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylsulfamate. LCMS: (AA) M+1 470; ¹H NMR (400 MHz, MeOD) b 8.48-8.40 (m,1H), 8.19 (d, J=5.5 Hz, 1H), 7.99-7.90 (m, 2H), 7.81-7.75 (m, 1H),7.60-7.47 (m, 3H), 6.69 (s, 1H), 6.37 (d, J=5.6 Hz, 1H), 4.24-4.06 (m,3H), 4.04-3.99 (m, 1H), 3.96-3.89 (m, 1H), 2.55-2.45 (m, 1H), 2.45-2.35(m, 1H), 1.60-1.48 (m, 1H).

Example 2b-A. Synthesis of(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylrel-sulfamate (I-2)

The procedure of Method A is followed except(rac)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanolinstead of(s.e.)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol.LCMS: (AA) M+1 470; ¹H NMR (400 MHz, MeOD) δ 8.48-8.40 (m, 1H), 8.19 (d,J=5.5 Hz, 1H), 7.99-7.90 (m, 2H), 7.81-7.75 (m, 1H), 7.60-7.47 (m, 3H),6.69 (s, 1H), 6.37 (d, J=5.6 Hz, 1H), 4.24-4.06 (m, 3H), 4.04-3.99 (m,1H), 3.96-3.89 (m, 1H), 2.55-2.45 (m, 1H), 2.45-2.35 (m, 1H), 1.60-1.48(m, 1H).

Method B [Example 2b-B] Example 2b-B. Alternative synthesis of(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylrel-sulfamate (I-2)

Step 1: 1-Naphthoylacetonitrile

To a solution of 2.50 M of n-butyllithium in hexane (49.9 mL, 125 mmol)in tetrahydrofuran (49.9 mL) cooled to −78° C. is added acetonitrile(6.52 mL, 125 mmol) drop-wise. The resulting cloudy mixture is stirredfor 30 min. Ethyl α-napthoate (8.87 mL, 49.9 mmol) is added drop-wiseand the reaction mixture is stirred at −78° C. for 2 hr. The reaction iswarmed to room temperature, quenched with acetic acid (50 ml) andpartitioned between ethyl acetate and water. The organic layer is driedover Na₂SO₄, filtered and concentrated in vacuo. The crude material ispurified by column chromatography (eluent: 5-15% CH₂Cl₂/methanol) toprovide 1-naphthoylacetonitrile (6.99 g, yield 72%). ¹H NMR (400 MHz,CDCl₃) δ 8.82 (d, J=8.7 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.90 (t, J=8.1Hz, 2H), 7.71-7.64 (m, 1H), 7.57 (dt, J=15.5, 7.2 Hz, 2H), 4.21 (s, 2H).

Step 2: Ethyl2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate

1-Naphthoylacetonitrile (161 mg, 0.825 mmol) and hydrazine (0.11 mL, 3.5mmol) are heated in ethanol (1.1 mL) at 70° C. in a sealed vial for 60hr. The reaction is cooled to room temperature and the solvent isremoved. The crude material is taken up in 5 ml of ethyl acetate andwashed with water and brine. The organic layer is concentrated in vacuoto give 3-(1-naphthyl)-1H-pyrazol-5-amine which is dissolved in aceticacid (0.375 mL, 6.60 mmol). Diethyl ethoxymethylenemalonate (0.182 mL,0.907 mmol) is added and the mixture is heated at 120° C. for 3 hr in asealed vial. During the reaction, a precipitate forms. The reaction iscooled to room temperature and the solid is collected in a Buchnerfunnel and washed with reagent grade alcohol to provide ethyl2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate(166 mg, yield 60%). ¹H NMR (300 MHz, DMSO) δ 8.73-8.66 (m, 1H), 8.64(s, 1H), 8.02 (dd, J=8.9, 3.4 Hz, 2H), 7.87-7.78 (m, 1H), 7.68-7.52 (m,3H), 6.71 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).

Step 3:2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylicacid

Ethyl2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate(163 mg, 0.489 mmol) is stirred in 4 M NaOH (2.4 mL) and ethanol (1.2mL) at 100° C. in a sealed vial for 5 hr during which time a precipitateforms. The reaction mixture is diluted with water and a saturatedsolution of ammonium chloride to bring the pH to about 4. Theprecipitate is collected in a Buchner funnel to provide2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylicacid (145 mg, yield 97%). ¹H NMR (400 MHz, DMSO) δ 8.74 (s, 1H),8.72-8.64 (m, 1H), 8.03 (dd, J=11.4, 5.4 Hz, 2H), 7.86 (d, J=6.3 Hz,1H), 7.69-7.52 (m, 3H), 6.80 (s, 1H).

Step 4: 2-(naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one

2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylicacid (2.00 g, 6.55 mmol) is stirred in dimethyl sulfoxide (5.06 mL, 71.2mol) in a 350 mL sealed reaction vessel. Sodium chloride (0.545 g, 9.33mol) is dissolved in water (2.26 mL) and added to the reaction mixture.The reaction is heated at 150° C. for 3 days during which time anadditional 8 mL of DMSO is added along with 15 mL of additional water.The resulting precipitate is collected in a Buchner funnel to provide2-(naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (1.48 g, 87%).LCMS: (AA) M+1 262.

Step 5: 7-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine

2-(naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (4.0 g, 15 mmol)is heated in phosphoryl chloride (28 mL) in a sealed vial at 105° C. andstirred for 5 hours. The crude reaction mixture is cooled to roomtemperature and poured slowly over ice. The resulting solid is collectedon a Buchner funnel to provide7-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine (4.3 g, yield 100%).LCMS: (AA) M+1 280.

Step 6:(rac)-(1S,2R,3R,5R)-3-(hydroxymethyl)-5-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentane-1,2-diylreldi-benzoate

A mixture of(rac)-(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diylreldi-benzoate hydrochloride (0.300 g, 0.767 mmol; obtained as theracemic mixture utilizing the method described in PCT Publication No.WO2008/019124), 7-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine (0.165g, 0.590 mmol) and N,N-diisopropylethylamine (0.360 mL, 2.06 mmol) inN-methylpyrrolidine (0.80 mL) is heated in a sealed reaction vial at 90°C. and stirred for 2 hr. The reaction mixture is cooled to roomtemperature and partitioned between ethyl acetate and water. The organiclayer is dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue is purified by column chromatography (eluent: 0-60% ethylacetate/hexanes) to provide(rac)-(1S,2R,3R,5R)-3-(hydroxymethyl)-5-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentane-1,2-diylreldi-benzoate (0.086 g, yield 24%). LCMS: (AA) M+1 599; ¹H NMR (300MHz, CDCl₃) δ 8.69-8.57 (m, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.09-7.98 (m,2H), 7.97-7.84 (m, 4H), 7.83-7.78 (m, 1H), 7.63-7.32 (m, 10H), 6.82 (s,1H), 6.34 (d, J=5.3 Hz, 1H), 5.76-5.66 (m, 1H), 5.65-5.57 (m, 1H),4.41-4.28 (m, 1H), 3.97-3.84 (m, 1H), 3.80-3.66 (m, 1H), 3.19-3.07 (m,1H), 2.75-2.59 (m, 2H), 1.92-1.80 (m, 1H).

Step 7:(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylrel-sulfamate (I-2)

To a solution of(1S,2R,3R,5R)-3-(hydroxymethyl)-5-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentane-1,2-diylreldi-benzoate (0.243 g, 0.406 mmol) in N,N-dimethylformamide (2.4 mL)cooled to 0° C. is added chlorosulfonamide (141 mg, 1.22 mmol) Thereaction mixture is stirred for 1 hr and then concentrated in vacuo. 1.0M NaOH (2 mL) and methanol (2 mL) are added and the reaction is stirredat room temperature until benzoate hydrolysis is complete. The reactionmixture is concentrated in vacuo and the residue suspended in methanoland filtered through a syringe filter. The crude materiel is purified bycolumn chromatography (eluent: 0-8% MeOH:CH₂Cl₂) to provide(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylrel-sulfamate (59 mg, yield 31%). LCMS: (AA) M+1 470; ¹H NMR (400 MHz,MeOD) δ 8.48-8.40 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 7.99-7.90 (m, 2H),7.81-7.75 (m, 1H), 7.60-7.47 (m, 3H), 6.69 (s, 1H), 6.37 (d, J=5.6 Hz,1H), 4.24-4.06 (m, 3H), 4.04-3.99 (m, 1H), 3.96-3.89 (m, 1H), 2.55-2.45(m, 1H), 2.45-2.35 (m, 1H), 1.60-1.48 (m, 1H).

Method C [Example 3] Example 3. Synthesis of(s.e.)-[(1R,2R,3S,4R)-4-{[2-(4-chloro-1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylsulfamate (I-108)

Step 1:(s.e.)-((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

To a solution of(s.e.)-{(3aR,4R,6R,6aS)-6-[(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(500 mg, 1.30 mmol) in 1,4-dioxane (8.0 mL) is addedbis(pinacolato)diboron (663 mg, 2.61 mol),bis(triphenylphosphine)palladium(II) chloride (102 mg, 1.46 mmol) andpotassium acetate (630 mg, 6.40 mmol) The mixture is heated at 100° C.for 20 hr during which time additionalbis(triphenylphosphine)palladium(II) chloride (114 mg) is added in twoportions. The reaction mixture is cooled to room temperature, dilutedwith ethyl acetate and filtered through celite to provide(s.e.)-((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(2 g) which is used without purification.

Step 2:(s.e.)-[(3aR,4R,6R,6aS)-6-{[2-(4-chloro-1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol

A microwave vial is charged with((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol(0.25 g, 0.58 mmol), 1-chloro-4-iodo-naphthalene (0.38 g, 1.30 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (29 mg, 0.036 mmol), cesium carbonate (0.70g, 2.2 mmol) 1,4-dioxane (4.0 mL, 50 mmol) and water (0.60 mL, 30 mmol).The reaction mixture is heated in the microwave at 110° C. for 30minutes and then cooled to room temperature. The reaction mixture isdiluted with ethyl acetate and was washed successively with water,saturated sodium bicarbonate solution and brine. The organic layer isdried over sodium sulfate, filtered and concentrated in vacuo. The crudematerial is purified by column chromatography (0-80% ethylactate/hexanes) to provide(s.e.)-[(3aR,4R,6R,6aS)-6-{[2-(4-chloro-1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol(0.450 g, yield 167%). LCMS: (AA) M+1 465.

Step 3:(s.e.)-[(1R,2R,3S,4R)-4-{[2-(4-chloro-1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylsulfamate (I-108)

The title compound is synthesized from(s.e.)-[(3aR,4R,6R,6aS)-6-{[2-(4-chloro-1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanolfollowing Step 2 of Method A. LCMS: (AA) M+1 504; ¹H NMR (400 MHz, MeOD)δ 8.54 (d, J=7.8 Hz, 1H), 8.36 (d, J=8.5 Hz, 1H), 8.21 (d, J=5.5 Hz,1H), 7.79-7.58 (m, 4H), 6.70 (s, 1H), 6.40 (d, J=5.6 Hz, 1H), 4.26-4.10(m, 3H), 4.06-3.99 (m, 1H), 3.98-3.91 (m, 1H), 2.56-2.46 (m, 1H),2.46-2.35 (m, 1H), 1.61-1.50 (m, 1H).

Method D [Example 4] Example 4. Synthesis of(rac)-((1R,2R,3S,4R)-4-{[5-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-9)

Step 1: 7-hydroxy-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of 3-(1-naphthyl)-1H-pyrazol-5-amine (654 mg, 3.12 mmol)and dimethyl malonate (0.394 mL, 3.44 mmol) in anhydrous ethanol (9.44mL, 162 mmol) is added 0.5 M sodium methoxide in methanol (12.5 mL, 6.25mmol). The mixture is heated at 120° C. under a nitrogen atmosphereovernight. The reaction mixture is cooled to room temperature and thesolvent is removed in vacuo. The residue is suspended in water and theprecipitate is collected in a Buchner funnel to provide2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine,7-diol (534 mg, yield 62%).LCMS: (AA) M+1 278; ¹H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.73 (dd,J=8.2, 4.8 Hz, 1H), 7.99-7.88 (m, 2H), 7.72 (dd, J=7.1, 1.1 Hz, 1H),7.58-7.49 (m, 4H), 5.83 (s, 1H), 4.14 (s, 1H).

Step 2: 5,7-dichloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine

A mixture of 7-hydroxy-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one(534 mg, 1.92 mmol) N,N-diethylaniline (0.952 mL, 5.98 mmol), phosphoruspentachloride (205 mg, 0.986 mmol), and phosphoryl chloride (8.98 mL,96.3 mmol) is stirred at 120° C. for 20 hours. The reaction mixture iscooled to room temperature and poured over ice. The precipitate iscollected in a Buchner funnel to provide5,7-dichloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine (538 mg, yield89%). LCMS: (AA) M+1 314; ¹H NMR (400 MHz, DMSO) δ 8.68-8.61 (m, 1H),8.09-8.02 (m, 2H), 7.90 (dd, J=7.2, 1.2 Hz, 1H), 7.72 (s, 1H), 7.65 (dd,J=8.2, 7.2 Hz, 1H), 7.63-7.58 (m, 2H), 7.32 (s, 1H).

Step 3:(rac)-(1R,2S,3R,5R)-3-{[5-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-5-(hydroxymethyl)cyclopentane-1,2-diylrel-di-benzoate

A suspension of(rac)-(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diylreldi-benzoate hydrochloride (150 mg, 0.382 mmol),5,7-dichloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.318mmol), and N,N-diisopropylethylamine (0.166 mL, 0.955 mmol) intetrahydrofuran (1.05 mL) is heated in a sealed reaction vial at 80° C.for 2.5 hr. The reaction is cooled to room temperature and the solventis removed in vacuo. The crude material is purified by columnchromatography (eluent: 0-80% ethyl acetate:hexanes) to provide(rac)-(1R,2S,3R,5R)-3-{[5-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-5-(hydroxymethyl)cyclopentane-1,2-diylreldi-benzoate (118 mg, yield 59%). LCMS: (AA) M+1 633; ¹H NMR (400 MHz,CDCl₃) δ 8.57-8.52 (m, 1H), 8.01-7.97 (m, 2H), 7.94-7.89 (m, 2H),7.88-7.83 (m, 2H), 7.73 (dd, J=7.1, 1.1 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H),7.58-7.49 (m, 2H), 7.48-7.32 (m, 8H), 6.71 (s, 1H), 6.33 (s, 1H), 5.66(t, J=4.8 Hz, 1H), 5.55 (t, J=5.0 Hz, 1H), 4.27-4.18 (m, 1H), 3.85-3.79(m, 1H), 3.59-3.52 (m, 1H), 2.57-2.49 (m, 2H), 1.77-1.64 (m, 1H).

Step 4:(rac)-((1R,2R,3S,4R)-4-{[5-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-9)

The title compound is synthesized from(rac)-(1R,2S,3R,5R)-3-{[5-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-5-(hydroxymethyl)cyclopentane-1,2-diylrel di-benzoate following Step 7 of Method B (yield 19%). LCMS: (AA) M+1504; ¹H NMR (400 MHz, MeOD) δ 8.48-8.42 (m, 1H), 7.99-7.91 (m, 2H),7.81-7.76 (m, 1H), 7.61-7.50 (m, 3H), 6.65 (s, 1H), 6.43 (s, 1H),4.25-4.06 (m, 3H), 4.01 (t, J=6.0 Hz, 1H), 3.94 (t, J=5.3 Hz, 1H),2.54-2.34 (m, 2H), 1.57 (dt, J=12.6, 9.0 Hz, 1H).

Method E [Example 5] Example 5. Synthesis of(rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl}methylrel-sulfamate (I-4)

Step 1: 5-Methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one

A mixture of 5-phenyl-1H-pyrazol-3-ylamine (501 mg, 3.15 mmol) and3-oxobutanoic acid ethyl ester (0.433 mL, 3.39 mmol) in anhydroustoluene (2.9 mL) is heated at 120° C. in a sealed vial. After 2 hr, thereaction is cooled to room temperature. The precipitate is collected ina Buchner funnel and washed with hexanes to afford5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (577 mg, yield 81%).LCMS: (AA) M+1 226; ¹H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 8.01-7.92(m, 2H), 7.49-7.43 (m, 2H), 7.42-7.37 (m, 1H), 6.57 (s, 1H), 5.60 (s,1H), 2.29 (s, 3H).

Step 2: 7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine

5-Methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (210 mg, 0.932 mmol)is heated in phosphoryl chloride (1.74 mL, 18.6 mmol) in a sealed vialat 100° C. for 2 hr. The reaction mixture is cooled to room temperatureand slowly poured over ice. The resulting suspension is extracted withdichloromethane and washed with brine. The organic layer is dried overNa₂SO₄, filtered and concentrated in vacuo. The crude material ispurification by column chromatography (eluent 0-100% ethylacetate:hexanes) to provide7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine (123 mg, yield 54%).LCMS: (AA) M+1 244; ¹H NMR (400 MHz, DMSO) δ 8.07-8.02 (m, 2H),7.53-7.47 (m, 2H), 7.46-7.41 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 2.53(s, 3H).

Step 3:(rac)-(1S,2R,3R,5R)-3-(hydroxymethyl)-5-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentane-1,2-diylreldi-benzoate

The title compound is synthesized from7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine following Step 3from Method D except DMF is used instead of THF. LCMS: (AA) M+1 563; ¹HNMR (400 MHz, MeOD) δ 8.06-7.97 (m, 3H), 7.88 (d, J=7.7 Hz, 2H),7.62-7.49 (m, 2H), 7.46-7.29 (m, 8H), 6.62 (s, 1H), 6.24 (s, 1H),5.70-5.58 (m, 2H), 4.60-4.50 (m, 1H), 3.91-3.81 (m, 1H), 3.80-3.72 (m,1H), 2.78-2.65 (m, 2H), 2.34 (s, 3H), 1.95-1.82 (m, 1H).

Step 4:(rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl}methylrel-sulfamate (I-4)

The title compound is synthesized from(rac)-(1S,2R,3R,5R)-3-(hydroxymethyl)-5-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentane-1,2-diylreldi-benzoate following Step 7 from Method B (yield 35%). LCMS: (AA)M+1 434; ¹H NMR (400 MHz, MeOD) δ 8.00 (d, J=7.4 Hz, 2H), 7.44 (t, J=7.5Hz, 2H), 7.37 (t, J=7.2 Hz, 1H), 6.63 (s, 1H), 6.21 (s, 1H), 4.28-4.17(m, 2H), 4.12-4.04 (m, 1H), 4.03-3.95 (m, 2H), 2.58-2.36 (m, 5H),1.62-1.50 (m, 1H).

Method F [Example 6] Example 6. Synthesis of(rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl}methylrel-sulfamate (I-89)

Step 1: 7-hydroxy-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-5(4H)-one

To a solution of dimethyl methylmalonate (1.30 mL, 9.80 mmol) and5-amino-3-phenylpyrazole (1.50 g, 9.42 mmol) in methanol (11 mL) isadded 25% sodium methoxide in methanol (6.04 mL, 26.4 mmol). Thereaction mixture is heated at 75° C. for 48 hr. The precipitate wascollected in a Buchner funnel and washed with dichloromethane to provide7-hydroxy-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-5(4H)-one (2.87 g,yield 95%). LCMS: (AA) M+1 242; ¹H NMR (400 MHz, DMSO) δ 10.39 (s, 1H),7.92-7.86 (m, 2H), 7.41-7.33 (m, 2H), 7.32-7.26 (m, 1H), 5.92 (s, 1H),1.75 (s, 3H).

Step 2: 5,7-dichloro-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine

The title compound is synthesized from7-hydroxy-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-5(4H)-one followingStep 2 from Method D (yield 61%).

Step 3:(rac)-(1R,2S,3R,5R)-3-[(5-chloro-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diylreldi-benzoate

The title compound is synthesized from5,7-dichloro-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine following Step 3from Method D except DMF is used instead of THF (yield 85%). LCMS: (AA)M+1 597.

Step 4:(rac)-{(1R,2R,3S,4R)-4-[(5-chloro-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methylrel-sulfamate

The title compound is synthesized from(rac)-(1R,2S,3R,5R)-3-[(5-chloro-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diylreldi-benzoate following Step 7 from Method B (yield 74%). LCMS: (AA)M+1 468.

Step 5:(rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(6-methyl-2-phenylpyrazzol[1,5-a]pyrimidin-7-yl)amino]cyclopentyl}methylrel-sulfamate (I-89)

A pressure bottle is charged with(rac)-{(1R,2R,3S,4R)-4-[(5-chloro-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methylrel-sulfamate (111 mg, 0.237 mmol), tetrahydrofuran (1.4 mL) and Pd [10%on carbon/50% water wet; Degussa type) 76 mg, 0.036 mmol)]. The reactionis stirred at room temperature under an atmosphere of hydrogen (30 psi)for 18 hr. The reaction mixture is filtered through celite andconcentrated in vacuo. The crude material is purified by preparativeHPLC to provide(rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl}methylrel-sulfamate (15 mg, yield 13%). LCMS: (FA) M+1 434; ¹H NMR (400 MHz,MeOD) δ 8.05-7.98 (m, 2H), 7.94 (s, 1H), 7.43 (t, J=7.4 Hz, 2H), 7.36(t, J=7.3 Hz, 1H), 6.69 (s, 1H), 4.20 (t, J=7.8 Hz, 2H), 4.03-3.94 (m,2H), 2.64 (s, 1H), 2.54-2.31 (m, 5H), 1.64-1.51 (m, 1H).

Example 7. Compounds Prepared by Method A(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methylrel-sulfamate (I-32)

The title compound is prepared using{1-[tert-butyl(dimethyl)silyl]-1H-indol-3-yl}boronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 459; ¹H NMR (400MHz, MeOD) δ 8.31-8.26 (m, 1H), 8.10 (d, J=5.5 Hz, 1H), 7.86 (s, 1H),7.46-7.40 (m, 1H), 7.22-7.14 (m, 2H), 6.70 (s, 1H), 6.28 (d, J=5.6 Hz,1H), 4.29-4.19 (m, 2H), 4.17-4.09 (m, 1H), 4.07 (t, J=5.8 Hz, 1H), 4.00(t, J=5.4 Hz, 1H), 2.61-2.50 (m, 1H), 2.48-2.37 (m, 1H), 1.67-1.56 (m,1H).

(rac)-[(1R,2R,3S,4R)-4-{[2-(9H-carbazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-37)

The title compound is prepared using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 509; ¹H NMR (400 MHz, MeOD) δ8.78 (s, 1H), 8.19-8.03 (m, 3H), 7.51 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.1Hz, 1H), 7.38 (dd, J=8.1, 7.1 Hz, 1H), 7.18 (t, J=7.4 Hz, 1H), 6.82 (s,1H), 6.29 (d, J=5.5 Hz, 1H), 4.31-4.20 (m, 2H), 4.16-3.97 (m, 3H),2.61-2.49 (m, 1H), 2.49-2.37 (m, 1H), 1.68-1.55 (m, 1H).

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methylrel-sulfamate (I-38)

The title compound is prepared using 5-methyl-2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 517; ¹H NMR (300 MHz, MeOD) δ8.17 (d, J=5.5 Hz, 1H), 8.06-7.93 (m, 2H), 7.56-7.41 (m, 3H), 6.83 (s,1H), 6.36 (d, J=5.5 Hz, 1H), 4.34-3.95 (m, 5H), 2.84 (s, 3H), 2.73-2.34(m, 2H), 1.70-1.53 (m, 1H).

(rac)-[(1R,2R,3S,4R)-4-{[2-(5-chloro-1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-54)

The title compound is prepared using 1-boc-5-chloroindole-3-boronic acidpinacol ester in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA)M+1 493; ¹H NMR (300 MHz, MeOD) δ 8.28 (d, J=2.0 Hz, 1H), 8.10 (d, J=5.5Hz, 1H), 7.91 (s, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.15 (d, J=10.6 Hz, 1H),6.68 (s, 1H), 6.28 (d, J=5.5 Hz, 1H), 4.32-3.94 (m, 5H), 2.62-2.34 (m,2H), 1.68-1.48 (m, 1H).

(rac)-[(1R,2R,3S,4R)-4-{[2-(6-chloro-1H-indol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-55)

The title compound is prepared using 1-boc-6-chloroindole-3-boronic acidpinacol ester in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA)M+1 493; ¹H NMR (300 MHz, MeOD) δ 8.30 (d, J=8.5 Hz, 1H), 8.08 (d, J=5.5Hz, 1H), 7.87 (s, 1H), 7.44 (s, 1H), 7.14 (d, J=8.6 Hz, 1H), 6.67 (s,1H), 6.25 (d, J=5.5 Hz, 1H), 4.31-4.18 (m, 2H), 4.17-3.95 (m, 3H),2.60-2.36 (m, 2H), 1.66-1.50 (m, 1H).

(rac)-[(1R,2R,3S,4R)-4-{[2-(9H-carbazol-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-62)

The title compound is prepared using 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 509; ¹H NMR (400 MHz, MeOD) δ8.14-8.03 (m, 4H), 7.88-7.83 (m, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.41-7.34(m, 1H), 7.20-7.13 (m, 1H), 6.82 (s, 1H), 6.28 (d, J=5.6 Hz, 1H),4.29-4.19 (m, 2H), 4.15-3.97 (m, 3H), 2.58-2.48 (m, 1H), 2.48-2.36 (m,1H), 1.65-1.54 (m, 1H).

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(2-phenyl-1,3-oxazol-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methylrel-sulfamate (I-67)

The title compound is prepared using2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-oxazole in Step1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 487; ¹H NMR (300MHz, MeOD) δ 8.22-8.09 (m, 3H), 7.80 (s, 1H), 7.59-7.51 (m, 3H), 6.81(s, 1H), 6.39 (d, J=5.6 Hz, 1H), 4.31-4.19 (m, 2H), 4.18-4.08 (m, 1H),4.07-3.96 (m, 2H), 2.57-2.37 (m, 2H), 1.67-1.56 (m, 1H).

(s.e)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-({2-[2-methoxy-5-(trifluoromethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclopentyl]methylsulfamate (I-102)

The title compound is prepared using2-Methoxy-5-(trifluoromethoxy)phenylboronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 534; ¹H NMR (400 MHz, DMSO) δ8.22 (d, J=3.1 Hz, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.75 (s, 1H), 7.56-7.33(m, 3H), 7.27 (d, J=9.2 Hz, 1H), 6.97 (s, 1H), 6.29 (d, J=5.4 Hz, 1H),5.04 (d, J=5.4 Hz, 1H), 4.82 (s, 1H), 4.17-4.00 (m, 2H), 4.00-3.94 (m,2H), 3.81-3.73 (m, 1H), 3.32 (s, 3H), 2.38-2.18 (m, 2H), 1.57-1.45 (m,1H).

(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-10)

The title compound is prepared using dibenzothiophene-4-boronic acid inStep 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 510; ¹H NMR(400 MHz, MeOD) δ 8.40-8.34 (m, 1H), 8.18 (d, J=5.5 Hz, 1H), 8.10-8.04(m, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.58-7.37 (m, 3H), 7.31 (s, 1H), 6.37(d, J=5.6 Hz, 1H), 4.30-4.21 (m, 2H), 4.19-4.11 (m, 1H), 4.10-4.05 (m,1H), 4.03-3.99 (m, 1H), 2.62-2.50 (m, 1H), 2.49-2.38 (m, 1H), 1.69-1.57(m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-103)

The title compound is prepared using dibenzothiophene-4-boronic acid inStep 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 510; ¹H NMR(400 MHz, MeOD) δ 8.40-8.34 (m, 1H), 8.18 (d, J=5.5 Hz, 1H), 8.10-8.04(m, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.58-7.37 (m, 3H), 7.31 (s, 1H), 6.37(d, J=5.6 Hz, 1H), 4.30-4.21 (m, 2H), 4.19-4.11 (m, 1H), 4.10-4.05 (m,1H), 4.03-3.99 (m, 1H), 2.62-2.50 (m, 1H), 2.49-2.38 (m, 1H), 1.69-1.57(m, 1H).

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1H-indol-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methylrel-sulfamate (I-74)

The title compound is prepared using 5-indolyl boronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 459; ¹H NMR (300MHz, MeOD) δ 8.29 (s, 1H), 8.18 (d, J=7.0 Hz, 1H), 7.93-7.76 (m, 1H),7.48 (d, J=8.5 Hz, 1H), 7.35-7.25 (m, 1H), 6.89 (s, 1H), 6.61 (d, J=7.1Hz, 1H), 6.57-6.53 (m, 1H), 4.44-4.18 (m, 3H), 4.17-4.10 (m, 1H),4.04-3.98 (m, 1H), 2.54-2.35 (m, 2H), 1.82-1.63 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate (I-101)

The title compound is prepared using trifluoromethylthio-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 520; ¹H NMR (400 MHz, MeOD) δ8.41 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 8.14 (d, J=5.4 Hz, 1H), 7.71 (d,J=7.8 Hz, 1H), 7.65-7.54 (m, 1H), 6.83 (s, 1H), 6.34 (d, J=5.5 Hz, 1H),4.30-3.92 (m, 5H), 2.57-2.34 (m, 2H), 1.67-1.52 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-44)

The title compound is prepared using trifluoromethylthio-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 520; ¹H NMR (400 MHz, MeOD) δ8.41 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 8.14 (d, J=5.4 Hz, 1H), 7.71 (d,J=7.8 Hz, 1H), 7.65-7.54 (m, 1H), 6.83 (s, 1H), 6.34 (d, J=5.5 Hz, 1H),4.30-3.92 (m, 5H), 2.57-2.34 (m, 2H), 1.67-1.52 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(4-fluoronaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-100)

The title compound is prepared using 4-fluoronaphthalene-1-boronic acidin Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 488; ¹HNMR (400 MHz, MeOD) δ 8.60-8.49 (m, 1H), 8.27-8.14 (m, 2H), 7.85-7.77(m, 1H), 7.70-7.61 (m, 2H), 7.37-7.26 (m, 1H), 6.71 (s, 1H), 6.42 (d,J=5.6 Hz, 1H), 4.28-4.12 (m, 3H), 4.08-4.03 (m, 1H), 4.01-3.96 (m, 1H),2.62-2.36 (m, 2H), 1.65-1.51 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(2-methoxy-5-(trifluoromethyl)phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methylrel-sulfamate (I-65)

The title compound is prepared using2-methoxy-5-(trifluoromethyl)phenylboronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (FA) M+1 518; ¹H NMR (400 MHz, DMSO) δ8.59-8.45 (m, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.91-7.70 (m, 2H), 7.60-7.30(m, 3H), 6.97 (s, 1H), 6.29 (d, J=5.4 Hz, 1H), 5.05 (s, 1H), 4.82 (s,1H), 4.22-4.07 (m, 1H), 4.07-3.89 (m, 5H), 3.81-3.69 (m, 1H), 2.37-2.16(m, 2H), 1.59-1.44 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(2-methoxy-5-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methylrel-sulfamate (I-66)

The title compound is prepared using2-methoxy-5-(trifluoromethoxy)phenylboronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (FA) M+1 534; ¹H NMR (400 MHz, DMSO) δ8.22 (d, J=3.0 Hz, 1H), 8.15 (d, J=5.3 Hz, 1H), 7.44-7.37 (m, 1H),7.29-7.23 (m, 1H), 6.97 (s, 1H), 6.28 (d, J=5.4 Hz, 1H), 4.16-4.08 (m,1H), 4.05-3.89 (m, 6H), 3.80-3.71 (m, 1H), 2.37-2.17 (m, 2H), 1.57-1.43(m, 1H).

(rac)-((1R,2R,3S,4R)-4-((2-(Benzo[b]thiophen-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-61)

The title compound is prepared using benzothiophene-4-boronic acidpinacol ester in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (FA)M+1 476; ¹H NMR (400 MHz, DMSO) δ 8.38 (d, J=5.5 Hz, 1H), 8.20-8.15 (m,2H), 8.07 (d, J=8.0 Hz, 1H), 7.95-7.91 (m, 1H), 7.87 (d, J=5.6 Hz, 1H),7.77-7.69 (m, 1H), 7.58-7.41 (m, 2H), 6.93 (s, 1H), 6.31 (d, J=5.4 Hz,1H), 4.17-4.09 (m, 1H), 4.07-3.93 (m, 4H), 3.81-3.74 (m, 2H), 2.41-2.18(m, 2H), 1.61-1.43 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(5-(trifluoromethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methylrel-sulfamate (I-60)

The title compound is prepared using5-(trifluoromethyl)thiophen-2-ylboronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (FA) M+1 494; ¹H NMR (400 MHz, DMSO) δ8.21-8.13 (m, 1H), 7.82-7.75 (m, 2H), 7.74-7.67 (m, 1H), 7.48 (s, 2H),6.98 (s, 1H), 6.31 (d, J=5.5 Hz, 1H), 5.06-5.00 (m, 1H), 4.84-4.77 (m,1H), 4.17-4.07 (m, 1H), 4.06-3.89 (m, 3H), 3.80-3.71 (m, 1H), 2.37-2.17(m, 2H), 1.53-1.42 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-((2-(Dibenzo[b,d]thiophen-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-56)

The title compound is prepared usingdibenzo[b,d]thiophen-4-ylboronicacid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (FA) M+1 526; ¹H NMR (300 MHz, DMSO) δ8.51-8.39 (m, 2H), 8.27-8.20 (m, 2H), 8.12-8.02 (m, 1H), 7.67 (t, J=7.7Hz, 1H), 7.61-7.42 (m, 4H), 7.39-7.27 (m, 1H), 7.13 (s, 1H), 6.39 (d,J=5.4 Hz, 1H), 4.21-4.13 (m, 1H), 4.11-3.97 (m, 3H), 3.86-3.76 (m, 1H),2.46-2.36 (m, 1H), 2.36-2.21 (m, 1H), 1.68-1.42 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-((2-(3-(Difluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-50)

The title compound is prepared using 3-(difluoromethoxy)-benzeneboronicacid in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 486;¹H NMR (300 MHz, DMSO) δ 8.15 (d, J=5.3 Hz, 1H), 8.00-7.93 (m, 1H),7.92-7.87 (m, 1H), 7.77-7.66 (m, 1H), 7.58-7.49 (m, 2H), 7.25-7.18 (m,1H), 6.97 (s, 1H), 6.28 (d, J=5.4 Hz, 1H), 5.12-4.94 (m, 1H), 4.90-4.72(m, 1H), 4.18-4.09 (m, 1H), 4.08-3.89 (m, 3H), 3.82-3.72 (m, 1H),2.40-2.17 (m, 2H), 1.57-1.40 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(3-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methylrel-sulfamate (I-51)

The title compound is prepared using4,4,5,5-tetramethyl-2-(3-phenoxyphenyl)-1,3,2-dioxaborolane in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 512; ¹H NMR (300MHz, DMSO) δ 8.13 (d, J=5.3 Hz, 1H), 7.92-7.82 (m, 2H), 7.49 (t, J=7.9Hz, 1H), 7.44-7.35 (m, 2H), 7.13 (t, J=7.4 Hz, 1H), 7.08-6.97 (m, 3H),6.93 (s, 1H), 6.26 (d, J=5.4 Hz, 1H), 4.20-4.07 (m, 1H), 4.07-3.86 (m,3H), 3.80-3.69 (m, 1H), 2.40-2.14 (m, 2H), 1.55-1.40 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-((2-(Benzo[b]thiophen-7-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-45)

The title compound is prepared using 1-benzothien-7-ylboronic acid inStep 1 instead of 1-naphthaleneboronic acid. LCMS: (FA) M+1 476; ¹H NMR(400 MHz, DMSO) δ 8.25 (s, 1H), 8.10 (d, J=7.3 Hz, 1H), 7.99 (d, J=7.2Hz, 1H), 7.88 (d, J=5.5 Hz, 1H), 7.59-7.46 (m, 4H), 7.26 (d, J=7.5 Hz,1H), 7.10 (s, 1H), 6.39 (d, J=5.2 Hz, 1H), 5.09 (d, J=5.6 Hz, 1H), 4.85(d, J=5.3 Hz, 1H), 4.23-4.12 (m, 1H), 4.11-3.95 (m, 3H), 3.86-3.76 (m,1H), 2.48-2.37 (m, 1H), 2.36-2.24 (m, 1H), 1.56-1.44 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(3-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methylrel-sulfamate (I-40)

The title compound is prepared using m-(trifluoromethoxy)phenylboronicacid in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 504;¹H NMR (300 MHz, DMSO) δ 8.20-8.04 (m, 3H), 7.67-7.58 (m, 1H), 7.44-7.36(m, 1H), 7.03 (s, 1H), 6.29 (d, J=5.4 Hz, 1H), 5.04 (s, 1H), 4.82 (s,1H), 4.18-4.08 (m, 1H), 4.08-3.89 (m, 3H), 3.82-3.72 (m, 1H), 2.39-2.17(m, 2H), 1.58-1.42 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(3-(pyridin-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methylrel-sulfamate (I-36)

The title compound is prepared using (3-pyridin-2-ylphenyl)boronic acidin Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 497; ¹HNMR (300 MHz, DMSO) δ 8.79-8.66 (m, 2H), 8.22-7.87 (m, 6H), 7.80-7.67(m, 1H), 7.66-7.56 (m, 1H), 7.45-7.36 (m, 1H), 7.02 (s, 1H), 6.28 (d,J=5.3 Hz, 1H), 4.20-3.95 (m, 4H), 3.82-3.74 (m, 1H), 3.40-3.34 (m, 1H),2.42-2.19 (m, 2H), 1.60-1.44 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-((2-(3-Bromophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-28)

The title compound is prepared using 3-bromophenylboronicacid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 498; ¹H NMR (300MHz, DMSO) δ 8.33 (s, 1H), 8.15 (d, J=5.3 Hz, 1H), 8.07 (d, J=7.8 Hz,1H), 7.78-7.71 (m, 1H), 7.63-7.57 (m, 1H), 7.51-7.40 (m, 3H), 6.99 (s,1H), 6.28 (d, J=5.4 Hz, 1H), 5.05-4.99 (m, 1H), 4.83-4.77 (m, 1H),4.18-4.09 (m, 1H), 4.07-3.91 (m, 3H), 3.81-3.73 (m, 1H), 2.40-2.17 (m,2H), 1.58-1.43 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-((2-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-29)

The title compound is prepared using2-fluoro-5-(trifluoromethyl)phenylboronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (FA) M+1 506; ¹H NMR (400 MHz, DMSO) δ8.64-8.58 (m, 1H), 8.20 (d, J=5.3 Hz, 1H), 7.94-7.84 (m, 2H), 7.67-7.59(m, 1H), 7.48 (s, 2H), 6.86 (d, J=4.2 Hz, 1H), 6.35 (d, J=5.4 Hz, 1H),5.04 (d, J=5.6 Hz, 1H), 4.81 (d, J=5.2 Hz, 1H), 4.17-4.08 (m, 1H),4.07-3.92 (m, 3H), 3.81-3.73 (m, 1H), 2.38-2.17 (m, 2H), 1.58-1.45 (m,1H).

(rac)-((1R,2R,3S,4R)-4-((2-(2-Chloro-5-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-30)

The title compound is prepared using2-chloro-5-(trifluoromethyl)phenylboronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (FA) M+1 522; ¹H NMR (400 MHz, DMSO) δ8.33-8.27 (m, 1H), 8.21 (d, J=5.3 Hz, 1H), 7.95-7.91 (m, 1H), 7.90-7.81(m, 2H), 7.47 (s, 2H), 6.95 (s, 1H), 6.34 (d, J=5.4 Hz, 1H), 5.02 (d,J=5.5 Hz, 1H), 4.80 (d, J=5.2 Hz, 1H), 4.17-4.06 (m, 1H), 4.06-3.90 (m,3H), 3.80-3.71 (m, 1H), 2.38-2.15 (m, 2H), 1.57-1.43 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(quinoin-8-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methylrel-sulfamate (I-17)

The title compound is prepared using 8-quinoline boronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (FA) M+1 471; ¹H NMR (400MHz, DMSO) δ 9.07-9.01 (m, 1H), 8.66-8.60 (m, 1H), 8.49-8.43 (m, 1H),8.18 (d, J=5.3 Hz, 1H), 8.10-8.03 (m, 1H), 7.79-7.70 (m, 2H), 7.65-7.57(m, 1H), 7.48 (s, 3H), 6.28 (d, J=5.3 Hz, 1H), 5.04 (d, J=5.5 Hz, 1H),4.81 (d, J=5.3 Hz, 1H), 4.18-4.08 (m, 1H), 4.08-3.91 (m, 3H), 3.83-3.72(m, 1H), 2.43-2.16 (m, 2H), 1.58-1.44 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(1-fluoronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-119)

The title compound is prepared using 2-(1-fluoro-2-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 488; ¹H NMR (400 MHz, DMSO) b8.47-8.41 (m, 1H), 8.22-8.16 (m, 2H), 8.04 (d, J=7.8 Hz, 1H), 7.90 (d,J=8.7 Hz, 1H), 7.81 (s, 1H), 7.72-7.63 (m, 2H), 6.94 (d, J=4.0 Hz, 1H),6.32 (d, J=5.4 Hz, 1H), 5.07 (s, 1H), 4.84 (s, 1H), 4.20-4.10 (m, 1H),4.07-3.95 (m, 3H), 3.82-3.74 (m, 1H), 2.38-2.23 (m, 2H), 1.57-1.47 (m,1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(4-fluoronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-118)

The title compound is prepared using 2-(4-fluoro-2-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 488; ¹H NMR (400 MHz, DMSO) b8.51 (s, 1H), 8.16 (d, J=5.3 Hz, 1H), 8.15-8.05 (m, 3H), 7.70-7.62 (m,2H), 7.10 (s, 1H), 6.29 (d, J=5.4 Hz, 1H), 5.75 (s, 1H), 5.05 (s, 1H),4.14 (dd, J=9.7, 5.9 Hz, 1H), 4.07-3.93 (m, 3H), 3.81-3.75 (m, 1H),2.39-2.21 (m, 2H), 1.58-1.48 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(3-fluoronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-116)

The title compound is prepared using 2-(3-fluoro-2-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 488; ¹H NMR (400 MHz, DMSO) b8.80 (d, J=7.7 Hz, 1H), 8.19 (d, J=5.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H),7.96 (d, J=8.0 Hz, 1H), 7.92-7.85 (m, 1H), 7.62-7.52 (m, 3H), 6.86 (d,J=4.2 Hz, 1H), 6.33 (d, J=5.4 Hz, 1H), 5.75 (s, 1H), 5.05 (d, J=5.2 Hz,1H), 4.21-4.10 (m, 1H), 4.10-3.94 (m, 3H), 3.83-3.74 (m, 1H), 2.40-2.22(m, 2H), 1.60-1.47 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(6-fluoronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-113)

The title compound is prepared using 2-(6-fluoro-2-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 488; ¹H NMR (400 MHz, DMSO) b8.66 (s, 1H), 8.32 (d, J=8.6 Hz, 1H), 8.15 (t, J=4.7 Hz, 1H), 8.11-8.05(m, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.51-7.44 (m, 2H),7.03 (s, 1H), 6.27 (t, J=5.7 Hz, 1H), 5.75 (s, 1H), 5.05 (d, J=5.3 Hz,1H), 4.82 (s, 1H), 4.19-4.11 (m, 1H), 4.09-3.94 (m, 3H), 3.82-3.74 (m,1H), 2.41-2.20 (m, 2H), 1.58-1.46 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(5-ethylbenzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-94)

The title compound is prepared using5-ethyl-1-benzothiophen-3-yl)boronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 504; ¹H NMR (400 MHz, DMSO) δ8.15 (t, J=5.1 Hz, 1H), 7.97 (d, J=4.1 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H),7.70 (s, 1H), 7.65 (s, 1H), 7.26 (dd, J=8.3, 1.6 Hz, 1H), 6.95 (d, J=4.8Hz, 1H), 6.29 (d, J=5.5 Hz, 1H), 5.04 (s, 1H), 4.80 (s, 1H), 4.20-4.09(m, 1H), 4.08-3.92 (m, 3H), 3.82-3.72 (m, 1H), 2.73 (q, J=7.5 Hz, 2H),2.38-2.19 (m, 3H), 1.56-1.43 (m, 1H), 1.25 (t, J=7.6 Hz, 3H).

(rac)-((1R,2R,3S,4R)-4-(2-(5-ethylbenzo[b]thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-95)

The title compound is prepared using(5-ethyl-1-benzothiophen-2-yl)boronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 504; ¹H NMR (400 MHz, DMSO) δ8.50 (s, 1H), 8.26 (s, 1H), 8.19 (d, J=5.3 Hz, 1H), 7.96 (d, J=8.3 Hz,1H), 7.71 (s, 1H), 7.33 (dd, J=8.3, 1.5 Hz, 1H), 6.91 (s, 1H), 6.31 (d,J=5.4 Hz, 1H), 4.19-4.09 (m, 1H), 4.05-3.92 (m, 3H), 3.78 (t, J=4.8 Hz,1H), 2.82 (q, J=7.6 Hz, 2H), 2.41-2.19 (m, 3H), 1.55-1.43 (m, 1H), 1.28(t, J=7.6 Hz, 3H).

(rac)-((1R,2R,3S,4R)-4-(2-(benzofuran-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-49)

The title compound is prepared using benzofuran-3-boronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 460; ¹H NMR (300MHz, DMSO) δ 8.65 (s, 1H), 8.57-8.46 (m, 1H), 8.16 (d, J=5.3 Hz, 1H),7.66 (dd, J=9.2, 3.6 Hz, 2H), 7.41 (dd, J=5.9, 3.2 Hz, 3H), 6.89 (s,1H), 6.30 (d, J=5.3 Hz, 1H), 4.22-4.11 (m, 1H), 4.09-3.95 (m, 3H),3.85-3.73 (m, 1H), 2.39-2.22 (m, 2H), 1.60-1.48 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(5-chlorobenzofuran-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-92)

The title compound is prepared using5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran inStep 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 494; ¹H NMR(300 MHz, DMSO) b 8.75 (s, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.16 (d, J=5.3Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.1 Hz, 1H), 6.31 (d,J=5.4 Hz, 1H), 4.21-4.11 (m, 1H), 4.09-3.94 (m, 3H), 3.82-3.75 (m, 1H),2.39-2.20 (m, 3H), 1.61-1.48 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(6-chlorobenzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-91)

The title compound is prepared using(6-chloro-1-benzothiophen-2-yl)boronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (FA) M+1 510; ¹H NMR (300 MHz, DMSO) δ8.89 (d, J=8.7 Hz, 1H), 8.39 (s, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.20-8.15(m, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.58-7.46 (m, 3H), 6.94 (s, 1H), 6.32(d, J=5.5 Hz, 1H), 5.04 (s, 1H), 4.83 (s, 1H), 4.21-4.10 (m, 1H),4.08-3.95 (m, 3H), 3.77 (s, 1H), 2.36-2.24 (m, 2H), 1.61-1.45 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(2-propoxypropan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-90)

The title compound is prepared using4,4,5,5-tetramethyl-2-[3-(2-propoxypropan-2-yl)phenyl]-1,3,2-dioxaborolanein Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 520.

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(2-oxopyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-87)

The title compound is prepared using1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-onein Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 503; ¹HNMR (300 MHz, DMSO) δ 8.21-8.08 (m, 2H), 7.91-7.82 (m, 1H), 7.80-7.70(m, 1H), 7.53-7.41 (m, 2H), 6.89 (s, 1H), 6.31-6.23 (m, 1H), 4.18-4.08(m, 1H), 4.06-3.90 (m, 5H), 3.81-3.73 (m, 1H), 2.61-2.51 (m, 2H),2.38-2.18 (m, 2H), 2.15-2.05 (m, 2H), 1.71 (s, 1H), 1.54-1.43 (m, 1H).(2 pyrrolidine protons under DMSO)

(rac)-((1R,2R,3S,4R)-4-(2-(6-chlorobenzo[b]thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-88)

The title compound is prepared using (6-chloro-1-benzothien-3-yl)boronicacid in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (FA) M+1 510;¹H NMR (300 MHz, DMSO) δ 8.17 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.89 (d,J=8.6 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.54-7.40 (m, 3H), 6.96 (d, J=7.0Hz, 1H), 6.31 (d, J=5.4 Hz, 1H), 5.04 (s, 1H), 4.80 (s, 1H), 4.19-4.09(m, 1H), 4.08-3.91 (m, 3H), 3.82-3.72 (m, 1H), 2.35-2.20 (m, 2H),1.60-1.43 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(3-(2-ethoxypropan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-84)

The title compound is prepared using2-[3-(1-ethoxy-1-methylethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 506; ¹HNMR (300 MHz, DMSO) δ 8.14 (d, J=5.3 Hz, 1H), 8.02 (s, 1H), 7.99-7.94(m, 1H), 7.45 (d, J=4.9 Hz, 2H), 6.90 (s, 1H), 6.26 (d, J=5.4 Hz, 1H),4.17-4.10 (m, 1H), 4.07-3.93 (m, 3H), 3.80-3.73 (m, 1H), 3.23-3.15 (m,3H), 2.39-2.19 (m, 2H), 1.53 (s, 6H), 1.10 (t, J=7.0 Hz, 3H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(2-methoxypropan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-82)

The title compound is prepared using2-[3-(1-methoxy-1-methylethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 492; ¹HNMR (300 MHz, DMSO) δ 8.13 (d, J=5.3 Hz, 1H), 8.03 (s, 1H), 7.96 (d,J=6.8 Hz, 1H), 7.49-7.39 (m, 2H), 6.90 (s, 1H), 6.29-6.22 (m, 1H),4.18-4.10 (m, 1H), 4.07-3.93 (m, 3H), 3.79-3.73 (m, 1H), 3.01 (s, 3H),2.38-2.22 (m, 2H), 1.52 (m, 7H).

(rac)-((1R,2R,3S,4R)-4-(2-(5-fluorobenzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-81)

The title compound is prepared using (5-fluoro-1-benzothien-3-yl)boronicacid in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (FA) M+1 494;¹H NMR (300 MHz, DMSO) δ 8.71-8.64 (m, 1H), 8.21-8.09 (m, 2H), 7.85-7.79(m, 1H), 7.52-7.45 (m, 1H), 7.39-7.31 (m, 1H), 6.95 (s, 1H), 6.34-6.29(m, 1H), 5.03 (s, 1H), 4.82 (s, 1H), 4.19-4.11 (m, 1H), 4.08-3.94 (m,3H), 3.81-3.75 (m, 1H), 2.39-2.21 (m, 2H), 1.60-1.50 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-78)

The title compound is prepared using 3-(morpholino)phenylboronic acid inStep 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 505; ¹H NMR(300 MHz, DMSO) δ 8.15-8.09 (m, 1H), 7.62 (s, 1H), 7.52 (s, 1H),7.35-7.29 (m, 1H), 6.99-6.93 (m, 1H), 6.91 (s, 1H), 6.28-6.22 (m, 1H),5.08 (s, 1H), 4.16-4.09 (m, 1H), 4.05-3.91 (m, 3H), 3.80-3.73 (m, 5H),3.23-3.17 (m, 4H), 2.37-2.20 (m, 2H), 1.53-1.45 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(piperidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-77)

The title compound is prepared using 3-(piperidino)phenylboronic acid inStep 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 503.

(rac)-((1R,2R,3S,4R)-4-(2-(3-benzoylphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-73)

The title compound is prepared using 3-benzoylphenylboronic acid pinacolester in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1524; ¹H NMR (300 MHz, DMSO) δ 8.44 (s, 1H), 8.40-8.33 (m, 1H), 8.19-8.12(m, 1H), 7.81-7.56 (m, 8H), 6.99 (s, 1H), 6.34-6.22 (m, 1H), 5.03 (s,1H), 4.80 (s, 1H), 4.17-4.07 (m, 1H), 4.06-3.90 (m, 3H), 3.80-3.68 (m,1H), 2.35-2.20 (m, 2H), 1.54-1.43 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(5-chlorobenzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-71)

The title compound is prepared using (5-chloro-1-benzothien-3-yl)boronicacid in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 510;¹H NMR (300 MHz, DMSO) δ 8.80-8.77 (m, 1H), 8.43 (s, 1H), 8.20-8.10 (m,2H), 7.89-7.82 (m, 1H), 7.52-7.47 (m, 1H), 6.93 (s, 1H), 6.34-6.29 (m,1H), 5.04 (s, 1H), 4.83 (s, 1H), 4.18-4.10 (m, 1H), 4.06-3.95 (m, 3H),3.81-3.75 (m, 1H), 2.38-2.22 (m, 2H), 1.59-1.48 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(3-benzylphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-69)

The title compound is prepared using 3-benzylphenylboronic acid pinacolester in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1510.

(rac)-[(1R,2R,3S,4R)-4-{[2-(3,3-dimethyl-1,3-dihydro-2-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-53)

The title compound is prepared using1,1-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2-benzofuranin Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 490; ¹HNMR (300 MHz, DMSO) δ 8.16-8.11 (m, 1H), 8.03-7.98 (m, 1H), 7.94 (s,1H), 7.52 (s, 1H), 7.37-7.33 (m, 1H), 6.92 (s, 1H), 6.27-6.23 (m, 1H),5.75 (s, 1H), 5.03 (s, 1H), 4.99 (s, 2H), 4.81 (s, 1H), 4.17-4.09 (m,1H), 4.07-3.92 (m, 3H), 3.81-3.74 (m, 1H), 2.39-2.21 (m, 2H), 1.48 (s,6H).

(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-19)

The title compound is prepared using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[b,d]furan in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 510; ¹H NMR (300 MHz, DMSO) b8.85 (s, 1H), 8.30-8.25 (m, 1H), 8.22-8.18 (m, 1H), 8.17-8.13 (m, 1H),7.83-7.78 (m, 1H), 7.76-7.72 (m, 1H), 7.58-7.44 (m, 4H), 7.01 (s, 1H),6.30-6.25 (m, 1H), 5.05-5.03 (m, 1H), 4.85-4.79 (m, 1H), 4.18-4.11 (m,1H), 4.08-3.96 (m, 3H), 3.82-3.76 (m, 1H), 2.41-2.25 (m, 2H), 1.60-1.48(m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(isoquinolin-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-18)

The title compound is prepared using 4-isoquinolineboronic acid in Step1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 471; ¹H NMR (300MHz, DMSO) δ 9.39 (s, 1H), 8.86 (s, 1H), 8.66-8.61 (m, 1H), 8.26-8.21(m, 2H), 7.91-7.84 (m, 1H), 7.79-7.73 (m, 1H), 6.90 (s, 1H), 6.38-6.33(m, 1H), 4.14-4.08 (m, 1H), 4.04-3.95 (m, 3H), 3.78-3.71 (m, 1H),2.39-2.21 (m, 2H), 1.57-1.47 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-46)

The title compound is prepared using1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine inStep 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 489.

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-42)

The title compound is prepared using quinoline-2-boronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 471; ¹H NMR (300MHz, DMSO) δ 8.17 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.89 (d, J=8.6 Hz,1H), 7.66 (d, J=7.4 Hz, 1H), 7.54-7.40 (m, 3H), 6.96 (d, J=7.0 Hz, 1H),6.31 (d, J=5.4 Hz, 1H), 5.04 (s, 1H), 4.80 (s, 1H), 4.19-4.09 (m, 1H),4.08-3.91 (m, 3H), 3.82-3.72 (m, 1H), 2.35-2.20 (m, 2H), 1.60-1.43 (m,1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-7-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-43)

The title compound is prepared using quinolin-7-ylboronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 471; ¹H NMR (300MHz, DMSO) δ 8.96-8.93 (m, 1H), 8.74 (s, 1H), 8.44-8.35 (m, 2H),8.19-8.16 (m, 1H), 8.13-8.06 (m, 1H), 7.57-7.48 (m, 2H), 7.15 (s, 1H),6.34-6.28 (m, 1H), 5.06-5.03 (m, 1H), 4.81 (s, 1H), 4.18-4.11 (m, 1H),4.08-3.96 (m, 3H), 3.79 (s, 1H), 3.17-3.14 (m, 1H), 2.40-2.22 (m, 2H),1.60-1.48 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(7-chloroquinolin-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-39)

The title compound is prepared using 7-chloroquinoline-4-boronic acidpinacol ester in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA)M+1 505; ¹H NMR (300 MHz, DMSO) δ 9.07-9.02 (m, 1H), 8.84-8.78 (m, 1H),8.28-8.23 (m, 1H), 8.20-8.15 (m, 1H), 7.92 (d, J=4.5 Hz, 1H), 7.75-7.68(m, 1H), 7.00 (s, 1H), 6.41-6.36 (m, 1H), 4.16-4.08 (m, 1H), 4.06-3.95(m, 3H), 3.79-3.72 (m, 1H), 2.39-2.20 (m, 2H), 1.57-1.46 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-6-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-34)

The title compound is prepared using quinoline-6-boronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 471; ¹H NMR (300MHz, DMSO) δ 8.94-8.90 (m, 1H), 8.68 (s, 1H), 8.57-8.49 (m, 1H),8.47-8.39 (m, 1H), 8.19-8.09 (m, 2H), 7.62-7.53 (m, 2H), 7.08 (s, 1H),6.33-6.26 (m, 1H), 5.04 (s, 1H), 4.17-4.10 (m, 1H), 4.08-3.94 (m, 3H),3.81-3.76 (m, 1H), 2.40-2.21 (m, 2H), 1.59-1.47 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(5-(trifluoromethyl)quinolin-8-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-33)

The title compound is prepared using5-trifluoromethylquinoline-8-boronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 539; ¹H NMR (300 MHz, DMSO) δ9.22-9.16 (m, 1H), 8.79-8.70 (m, 1H), 8.58 (d, J=8.7 Hz, 1H), 8.26-8.15(m, 2H), 7.88-7.78 (m, 1H), 7.54 (s, 2H), 6.36-6.28 (m, 1H), 5.03 (s,1H), 4.20-4.09 (m, 1H), 4.08-3.91 (m, 3H), 3.85-3.73 (m, 1H), 2.39-2.20(m, 2H), 1.60-1.45 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(isoquiniin-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-27)

The title compound is prepared using isoquinolin-5-ylboronic acid inStep 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 471; ¹H NMR(300 MHz, DMSO) δ 9.40 (s, 1H), 8.61-8.49 (m, 2H), 8.25-8.15 (m, 3H),7.82-7.78 (m, 1H), 7.45 (s, 1H), 6.87 (s, 1H), 6.38-6.30 (m, 1H),5.04-5.00 (m, 1H), 4.79 (m, 1H), 4.18-4.08 (m, 1H), 4.05-3.93 (m, 3H),3.75 (s, 1H), 2.40-2.21 (m, 2H), 1.59-1.45 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-25)

The title compound is prepared using 3-quinolineboronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (FA) M+1 471; ¹H NMR (300MHz, DMSO) δ 9.67 (s, 1H), 8.99 (s, 1H), 8.21-8.17 (m, 1H), 8.11-8.03(m, 2H), 7.84-7.77 (m, 2H), 7.62 (s, 1H), 7.49 (s, 2H), 7.19-7.11 (m,1H), 6.39-6.27 (m, 1H), 5.06-5.02 (m, 1H), 4.90-4.75 (m, 1H), 4.21-4.11(m, 1H), 4.08-3.92 (m, 3H), 3.85-3.75 (m, 1H), 2.36-2.27 (m, 1H),1.63-1.46 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(benzo[b]thiophen-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-22)

The title compound is prepared using thianaphthene-3-boronic acid inStep 1 instead of 1-naphthaleneboronic acid. (FA) M+1 476; ¹H NMR (300MHz, DMSO) δ 8.89-8.81 (m, 1H), 8.34 (s, 1H), 8.24-8.13 (m, 1H),8.10-8.02 (m, 1H), 7.66 (s, 1H), 7.55-7.44 (m, 3H), 6.93 (s, 1H),6.35-6.24 (m, 1H), 5.10-5.00 (m, 1H), 4.80 (s, 1H), 4.19-4.09 (m, 1H),4.09-3.94 (m, 3H), 3.84-3.72 (m, 1H), 2.39-2.22 (m, 2H), 1.63-1.45 (m,1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(naphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-16)

The title compound is prepared using 2-naphthaleneboronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 470; ¹H NMR (300MHz, DMSO) δ 8.63 (s, 1H), 8.30-8.26 (m, 1H), 8.17-8.14 (m, 1H),8.06-7.93 (m, 3H), 7.60-7.53 (m, 2H), 7.52-7.45 (m, 1H), 7.05 (s, 1H),6.32-6.26 (m, 1H), 5.06-5.02 (m, 1H), 4.85-4.76 (m, 1H), 4.20-4.11 (m,1H), 4.09-3.96 (m, 3H), 3.83-3.75 (m, 1H), 2.39-2.25 (m, 2H), 1.63-1.46(m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-72)

The title compound is prepared using 2-methoxyphenylboronic acid in Step1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 450; ¹H NMR (400MHz, DMSO) δ 8.26-8.21 (m, 1H), 8.13 (d, J=5.3 Hz, 1H), 7.74-7.60 (m,1H), 7.45-7.35 (m, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.09-7.02 (m, 1H), 6.89(s, 1H), 6.24 (d, J=5.4 Hz, 1H), 4.17-4.08 (m, 1H), 4.07-3.99 (m, 1H),3.98-3.93 (m, 2H), 3.91 (s, 3H), 3.79-3.72 (m, 1H), 2.39-2.27 (m, 1H),2.27-2.16 (m, 1H), 1.55-1.42 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-68)

The title compound is prepared using (2-phenoxyphenyl)boranediol in Step1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 512; ¹H NMR (400MHz, DMSO) δ 8.39-8.32 (m, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.51-7.43 (m,1H), 7.39-7.30 (m, 3H), 7.13-7.03 (m, 2H), 6.96 (d, J=7.8 Hz, 2H), 6.72(s, 1H), 6.25 (d, J=5.4 Hz, 1H), 4.19-4.08 (m, 1H), 4.08-3.99 (m, 1H),3.98-3.89 (m, 2H), 3.81-3.71 (m, 1H), 2.38-2.18 (m, 2H), 1.55-1.41 (m,1H).

(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-41)

The title compound is prepared using2-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 488; ¹HNMR (400 MHz, DMSO) δ 8.12 (d, J=5.3 Hz, 1H), 7.90-7.84 (m, 2H), 7.27(d, J=8.3 Hz, 1H), 6.87 (s, 1H), 6.24 (d, J=5.4 Hz, 1H), 4.19-4.08 (m,1H), 4.09-4.00 (m, 1H), 4.01-3.91 (m, 2H), 3.82-3.73 (m, 1H), 2.93-2.81(m, 2H), 2.39-2.28 (m, 1H), 2.28-2.17 (m, 1H), 1.97-1.88 (m, 2H),1.56-1.43 (m, 1H), 1.29 (s, 6H).

(rac)-((1R,2R,3S,4R)-4-(2-(5-chloro-2-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-57)

The title compound is prepared using5-chloro-2-(trifluoromethoxy)phenylboronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+1 538; ¹H NMR (400 MHz, DMSO) δ8.39 (d, J=2.7 Hz, 1H), 8.20 (d, J=5.3 Hz, 1H), 7.96-7.83 (m, 1H),7.67-7.61 (m, 1H), 7.61-7.54 (m, 1H), 6.76 (s, 1H), 6.35 (d, J=5.4 Hz,1H), 5.18-4.70 (m, 2H), 4.21-4.09 (m, 1H), 4.07-4.00 (m, 1H), 4.00-3.90(m, 2H), 3.81-3.70 (m, 1H), 2.39-2.16 (m, 2H), 1.59-1.44 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-26)

The title compound is prepared using3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuranin Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 490; ¹HNMR (400 MHz, DMSO) δ 8.10 (d, J=5.3 Hz, 1H), 7.94-7.88 (m, 1H),7.88-7.81 (m, 1H), 7.65-7.57 (m, 1H), 7.54-7.44 (m, 2H), 6.85 (d, J=8.3Hz, 1H), 6.80 (s, 1H), 6.22 (d, J=5.4 Hz, 1H), 5.19-4.93 (m, 1H),4.95-4.69 (m, 1H), 4.27 (s, 2H), 4.19-4.07 (m, 1H), 4.07-3.99 (m, 1H),3.99-3.89 (m, 2H), 3.85-3.70 (m, 1H), 2.39-2.28 (m, 1H), 2.28-2.17 (m,1H), 1.59-1.43 (m, 1H), 1.36 (s, 6H).

(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-23)

The title compound is prepared using3,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuranin Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 490; ¹HNMR (400 MHz, DMSO) δ 8.13 (d, J=5.3 Hz, 1H), 8.09-8.04 (m, 1H),7.69-7.60 (m, 1H), 7.52-7.44 (m, 2H), 7.26-7.21 (m, 1H), 7.03-6.96 (m,1H), 6.86 (s, 1H), 6.26 (d, J=5.4 Hz, 1H), 5.08-4.96 (m, 1H), 4.85-4.66(m, 1H), 4.39 (s, 2H), 4.19-4.07 (m, 1H), 4.08-3.99 (m, 1H), 3.98-3.91(m, 2H), 3.82-3.69 (m, 1H), 2.40-2.28 (m, 1H), 2.28-2.17 (m, 1H),1.56-1.42 (m, 1H), 1.34 (s, 6H).

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1H-indol-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methylrel-sulfamate (I-24)

The title compound is prepared using 2-pinacolateboryl indole in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 459; ¹H NMR (400MHz, DMSO) δ 11.56 (s, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.62-7.54 (m, 1H),7.49-7.36 (m, 2H), 7.17-7.08 (m, 1H), 7.06-6.97 (m, 2H), 6.88 (s, 1H),6.30 (d, J=5.4 Hz, 1H), 5.17-4.99 (m, 1H), 4.99-4.74 (m, 1H), 4.20-4.09(m, 1H), 4.09-4.01 (m, 1H), 4.01-3.87 (m, 2H), 3.84-3.68 (m, 1H),2.44-2.33 (m, 1H), 2.32-2.19 (m, 1H), 1.52-1.35 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(5-chloro-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-20)

The title compound is prepared using (5-chloro-2-methoxyphenyl)boronicacid in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 484;¹H NMR (400 MHz, DMSO) δ 8.35-8.25 (m, 1H), 8.14 (d, J=5.3 Hz, 1H),7.83-7.72 (m, 1H), 7.52-7.46 (m, 2H), 7.46-7.39 (m, 1H), 7.19 (d, J=9.0Hz, 1H), 6.94 (s, 1H), 6.27 (d, J=5.4 Hz, 1H), 5.09-4.96 (m, 1H),4.88-4.71 (m, 1H), 4.19-4.08 (m, 1H), 4.07-4.00 (m, 1H), 4.01-3.95 (m,2H), 3.94 (s, 3H), 3.81-3.66 (m, 1H), 2.37-2.18 (m, 2H), 1.56-1.40 (m,1H).

(rac)-((1R,2R,3S,4R)-4-(2-(5-chloro-2-methylphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-21)

The title compound is prepared using 5-chloro-2-methylphenylboronic acidin Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 468; ¹HNMR (400 MHz, DMSO) δ 8.17 (d, J=5.3 Hz, 1H), 7.84-7.69 (m, 2H),7.52-7.42 (m, 2H), 7.41-7.33 (m, 2H), 6.72 (s, 1H), 6.29 (d, J=5.4 Hz,1H), 5.08-4.92 (m, 1H), 4.86-4.66 (m, 1H), 4.17-4.06 (m, 1H), 4.06-3.98(m, 1H), 3.98-3.89 (m, 2H), 3.79-3.63 (m, 1H), 3.33 (s, 3H), 2.36-2.17(m, 2H), 1.55-1.39 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trimethylsilyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-35)

The title compound is prepared using 3-trimethylsilylphenylboronic acidin Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 492.3; ¹HNMR (400 MHz, DMSO) δ 8.18-8.12 (m, 2H), 8.11-8.06 (m, 1H), 7.68 (d,J=7.8 Hz, 1H), 7.55 (d, J=7.3 Hz, 1H), 7.51-7.42 (m, 3H), 6.94 (s, 1H),6.26 (d, J=5.4 Hz, 1H), 5.03 (d, J=5.6 Hz, 1H), 4.81 (d, J=5.2 Hz, 1H),4.13 (dd, J=9.7, 6.0 Hz, 1H), 4.06-3.89 (m, 3H), 3.77 (dd, J=10.0, 5.0Hz, 1H), 2.39-2.17 (m, 2H), 1.56-1.42 (m, 1H), 0.31 (s, 9H).

(rac)-{(1R,2R,3S,4R)-4-[(2-{3-[(cyclopropylmethyl)sulfanyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methylrel-sulfamate (I-76)

The title compound is prepared using3-(cyclopropylmethyl)thiophenylboronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+506; ¹H NMR (400 MHz, MeOD) δ8.13 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 7.90-7.73 (m, 1H), 7.45-7.30 (m,2H), 6.77 (s, 1H), 6.32 (d, J=5.6 Hz, 1H), 4.28-4.06 (m, 3H), 4.05-3.90(m, 2H), 2.99-2.83 (m, 2H), 2.55-2.29 (m, 2H), 1.63-1.44 (m, 1H),1.13-0.96 (m, 1H), 0.60-0.47 (m, 2H), 0.37-0.18 (m, 2H).

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1H-indol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methylrel-sulfamate (I-75)

The title compound is prepared using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole in Step 1 instead of 1-naphthaleneboronicacid. LCMS: (AA) M+459; ¹H NMR (400 MHz, MeOD) δ 8.15 (d, J=5.5 Hz, 1H),7.68-7.59 (m, 1H), 7.51-7.43 (m, 1H), 7.36 (d, J=3.2 Hz, 1H), 7.25-7.17(m, 1H), 7.14-7.09 (m, 1H), 6.85 (s, 1H), 6.33 (d, J=5.6 Hz, 1H),4.31-4.18 (m, 2H), 4.18-4.09 (m, 1H), 4.09-4.02 (m, 1H), 4.02-3.95 (m,1H), 2.61-2.49 (m, 1H), 2.49-2.36 (m, 1H), 1.69-1.54 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(4-fluoro-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-70)

The title compound is prepared using 4-fluoro-2-methoxyphenylboronicacid in Step 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+468;¹H NMR (300 MHz, MeOD) δ 8.27-8.16 (m, 1H), 8.12 (d, J=5.5 Hz, 1H),6.97-6.86 (m, 2H), 6.84-6.72 (m, 1H), 6.30 (d, J=5.6 Hz, 1H), 4.31-4.17(m, 2H), 4.15-3.91 (m, 6H), 2.61-2.33 (m, 2H), 1.69-1.50 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-(trifluoromethyl)pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-59)

The title compound is prepared using2-(trifluoromethyl)pyridine-4-boronic acid in Step 1 instead of1-naphthaleneboronic acid. LCMS: (AA) M+489; ¹H NMR (300 MHz, MeOD) δ8.78 (d, J=5.1 Hz, 1H), 8.62-8.46 (m, 1H), 8.35-8.22 (m, 1H), 8.19 (d,J=5.5 Hz, 1H), 7.05 (s, 1H), 6.40 (d, J=5.6 Hz, 1H), 4.35-3.88 (m, 5H),2.60-2.35 (m, 2H), 1.73-1.51 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-methoxy-5-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate (I-120)

The title compound is prepared using{2-methoxy-5-[(trifluoromethyl)sulfanyl]phenyl}boronic acid in Step 1instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 550; ¹H NMR (400MHz, MeOD) δ 8.58 (d, J=2.4 Hz, 1H), 8.17 (d, J=5.5 Hz, 1H), 7.82-7.61(m, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.02 (s, 1H), 6.36 (d, J=5.5 Hz, 1H),4.31-4.11 (m, 3H), 4.10-4.03 (m, 4H), 4.02-3.96 (m, 1H), 2.64-2.34 (m,2H), 1.71-1.51 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(2,4-dichloronaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-117)

The title compound is prepared using2-(2,4-dichloro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane inStep 1 instead of 1-naphthaleneboronic acid. LCMS: (AA) M+1 538; ¹H NMR(400 MHz, MeOD) δ 8.31 (d, J=8.5 Hz, 1H), 8.23 (d, J=5.5 Hz, 1H), 7.81(s, 1H), 7.70-7.58 (m, 2H), 7.56-7.48 (m, 1H), 6.56 (s, 1H), 6.41 (d,J=5.6 Hz, 1H), 4.23-4.07 (m, 3H), 4.02-3.95 (m, 1H), 3.95-3.87 (m, 1H),2.56-2.31 (m, 2H), 1.55-1.42 (m, 1H).

Example 8. Compounds prepared by Method B(rac)-((1R,2R,3S,4R)-4-(2-(biphenyl-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-3)

The title compound is prepared using methyl biphenyl-3-carboxylate inStep 1 instead of ethyl α-napthoate. LCMS: (AA) M+1 496; ¹H NMR (300MHz, MeOD) δ 8.39-8.30 (m, 1H), 8.13 (d, J=5.5 Hz, 1H), 8.04-7.95 (m,2H), 7.72-7.28 (m, 9H), 6.85 (s, 1H), 6.31 (d, J=5.6 Hz, 1H), 4.27-4.04(m, 3H), 4.01-3.87 (m, 2H), 2.56-2.30 (m, 2H), 1.59-1.43 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-phenylpyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-1)

The title compound is prepared starting from 5-amino-3-phenylpyrazoleand following Step 2b to Step 7. LCMS: (AA) M+1 420; ¹H NMR (300 MHz,MeOD) δ 8.12 (d, J=5.5 Hz, 1H), 8.07-7.99 (m, 2H), 7.49-7.36 (m, 3H),6.76 (s, 1H), 6.31 (d, J=5.6 Hz, 1H), 4.28-3.91 (m, 5H), 2.59-2.33 (m,2H), 1.67-1.51 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-((2-(3-(tert-Butyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-15)

The title compound is prepared using 3-tert-butylbenzoic acid ethylester in Step 1 instead of ethyl α-naphthoate. LCMS: (FA) M+1 476; ¹HNMR (400 MHz, DMSO) δ 8.13 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.90 (d,J=7.3 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.46-7.36 (m, 3H), 6.92 (s, 1H),6.26 (d, J=5.3 Hz, 1H), 5.04 (s, 1H), 4.82 (s, 1H), 4.18-4.08 (m, 1H),4.08-3.88 (m, 3H), 3.81-3.73 (m, 1H), 2.39-2.18 (m, 3H), 1.57-1.43 (m,1H), 1.36 (s, 9H).

(rac)-((1R,2R,3S,4R)-4-((2-(3-Chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-5)

The title compound is prepared using ethyl 3-chlorobenzoate in Step 1instead of ethyl α-napthoate. LCMS: (FA) M+1 454.

(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methylrel-sulfamate (I-7)

The title compound is prepared using 3-(trifluoromethyl)benzoic acid inStep 1 instead of ethyl α-napthoate. LCMS: M+1 488; ¹H NMR (400 MHz,MeOD) δ 8.40 (s, 1H), 8.32-8.24 (m, 1H), 8.19-8.11 (m, 1H), 7.73-7.61(m, 2H), 6.87 (s, 1H), 6.35 (d, J=5.5 Hz, 1H), 4.28-4.18 (m, 2H),4.18-4.09 (m, 1H), 4.08-4.03 (m, 1H), 4.01-3.96 (m, 1H), 2.58-2.35 (m,2H), 1.67-1.54 (m, 1H).

(rac)-[(1R,2R,3S,4R)-4-{[2-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-13)

The title compound is prepared starting from5-(2,4-dichloro-phenyl)₂H-pyrazol-3-ylamine hydrochloride and followingStep 2b to Step 7. LCMS: (AA) M+1 488; ¹H NMR (400 MHz, MeOD) δ 8.17 (s,1H), 8.03 (d, J=8.5 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.46-7.40 (m, 1H),6.90 (s, 1H), 6.37 (d, J=5.4 Hz, 1H), 4.27-4.17 (m, 2H), 4.16-4.07 (m,1H), 4.05-4.00 (m, 1H), 3.99-3.94 (m, 1H), 2.57-2.47 (m, 1H), 2.46-2.35(m, 1H), 1.65-1.51 (m, 1H).

Example 9. Compounds prepared by Method C(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-isopropoxynaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate (I-109)

The title compound is prepared using 1-bromo-2-isopropoxynaphthalene1-bromo-2-naphthyl isopropyl in Step 2 instead of1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 528; ¹H NMR (400 MHz, MeOD)δ 8.20 (d, J=5.5 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.87-7.80 (m, 1H),7.71-7.63 (m, 1H), 7.45 (d, J=9.1 Hz, 1H), 7.38-7.31 (m, 2H), 6.54 (s,1H), 6.37 (d, J=5.6 Hz, 1H), 4.67-4.59 (m, 1H), 4.23-4.06 (m, 3H),4.02-3.95 (m, 1H), 3.94-3.89 (m, 1H), 2.58-2.46 (m, 1H), 2.45-2.34 (m,1H), 1.56-1.44 (m, 1H), 1.20 (d, J=6.1 Hz, 6H).

(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-93)

The title compound is prepared using 3-bromodibenzo[b,d]furan in Step 2instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 510; ¹H NMR (400MHz, DMSO) δ 8.29 (d, J=7.9 Hz, 1H), 8.25 (d, J=5.3 Hz, 1H), 7.82-7.78(m, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.71-7.67 (m, 1H), 7.66-7.60 (m, 1H),7.56-7.50 (m, 1H), 7.34-7.25 (m, 1H), 6.85 (s, 1H), 6.37 (d, J=5.5 Hz,1H), 4.15-4.05 (m, 1H), 4.02-3.90 (m, 3H), 3.78-3.71 (m, 1H), 2.41-2.31(m, 1H), 2.29-2.19 (m, 1H), 1.54-1.42 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-{[2-(5-tert-butyl-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-63)

The title compound is prepared using4-tert-butyl-2-iodo-1-methoxybenzene in Step 2 instead of1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 506; ¹H NMR (400 MHz,DMSO+D20) δ 8.12 (d, J=5.3 Hz, 1H), 8.06-8.01 (m, 1H), 7.43-7.37 (m,1H), 7.06 (d, J=8.8 Hz, 1H), 6.82 (s, 1H), 6.24 (d, J=5.4 Hz, 1H),4.17-4.07 (m, 1H), 4.07-3.98 (m, 1H), 3.99-3.89 (m, 2H), 3.85 (s, 3H),3.79-3.70 (m, 1H), 2.37-2.28 (m, 1H), 2.28-2.18 (m, 1H), 1.52-1.42 (m,1H), 1.31 (s, 9H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(9-oxo-9H-fluoren-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-85)

The title compound is prepared using 2-Bromofluoren-9-one in Step 2instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 522; ¹H NMR (400MHz, DMSO) δ 8.42-8.36 (m, 1H), 8.35-8.29 (m, 1H), 8.15 (d, J=5.3 Hz,1H), 7.93 (d, J=7.8 Hz, 1H), 7.90-7.84 (m, 1H), 7.84-7.77 (m, 1H),7.69-7.62 (m, 2H), 7.58-7.44 (m, 2H), 7.45-7.36 (m, 1H), 7.05 (s, 1H),6.29 (d, J=5.4 Hz, 1H), 5.16-4.97 (m, 1H), 4.94-4.70 (m, 1H), 4.20-4.08(m, 1H), 4.08-3.92 (m, 3H), 3.85-3.71 (m, 1H), 2.40-2.19 (m, 2H),1.59-1.45 (m, 1H).

(rac)-(1R,2R,3S,4R)-4-(2-(3-cyclopentenylphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-47)

The title compound is prepared using1-bromo-3-cyclopent-1-en-1-ylbenzene in Step 2 instead of1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 486; ¹H NMR (400 MHz, DMSO)δ 8.21-8.09 (m, 2H), 7.99-7.91 (m, 1H), 7.74-7.64 (m, 1H), 7.51-7.41 (m,3H), 6.96 (s, 1H), 6.47-6.36 (m, 1H), 6.30-6.22 (m, 1H), 5.14-4.97 (m,1H), 4.91-4.73 (m, 1H), 4.19-4.09 (m, 1H), 4.08-3.89 (m, 3H), 3.83-3.72(m, 1H), 2.76 (d, m, 2H), 2.39-2.18 (m, 2H), 2.10-1.94 (m, 2H),1.61-1.41 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-58)

The title compound is prepared using1-iodo-3-(2,2,2-trifluoro-1,1-dimethylethyl)benzene in Step 2 instead of1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 530; ¹H NMR (400 MHz, DMSO)b 8.18-8.12 (m, 2H), 8.12-8.06 (m, 1H), 7.71-7.62 (m, 1H), 7.61-7.55 (m,1H), 7.55-7.48 (m, 2H), 7.00 (s, 1H), 6.28 (d, J=5.4 Hz, 1H), 5.13-4.94(m, 1H), 4.93-4.70 (m, 1H), 4.20-4.08 (m, 1H), 4.08-4.00 (m, 1H),4.00-3.90 (m, 2H), 3.82-3.66 (m, 1H), 2.40-2.29 (m, 1H), 2.28-2.16 (m,1H), 1.64 (s, 6H), 1.54-1.41 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(2-(difluoromethoxy)naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-110)

The title compound is prepared using1-bromo-2-(difluoromethoxy)naphthalene in Step 2 instead of1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 536; ¹H NMR (400 MHz, MeOD)δ 8.23 (d, J=5.5 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 8.01-7.89 (m, 1H),7.83-7.71 (m, 1H), 7.59-7.40 (m, 3H), 6.83 (t, J=74.5 Hz, 1H), 6.59 (s,1H), 6.42 (d, J=5.7 Hz, 1H), 4.24-4.08 (m, 3H), 4.03-3.96 (m, 1H),3.95-3.88 (m, 1H), 2.57-2.45 (m, 1H), 2.45-2.32 (m, 1H), 1.59-1.41 (m,1H).

(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(4-methylnaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate (I-115)

The title compound is prepared using 1-bromo-4-methylnaphthalene in Step2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 484; ¹H NMR(300 MHz, MeOD) δ 8.50-8.40 (m, 1H), 8.20 (d, J=5.5 Hz, 1H), 8.15-8.03(m, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.62-7.48 (m, 2H), 7.46-7.38 (m, 1H),6.66 (s, 1H), 6.38 (d, J=5.6 Hz, 1H), 4.29-4.08 (m, 3H), 4.05-3.99 (m,1H), 3.98-3.90 (m, 1H), 2.75 (s, 3H), 2.61-2.32 (m, 2H), 1.63-1.46 (m,1H).

(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-methylnaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate (I-114)

The title compound is prepared using 1-bromo-2-methylnaphthalene in Step2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 484; ¹H NMR(400 MHz, MeOD) δ 8.19 (d, J=5.5 Hz, 1H), 7.93-7.79 (m, 2H), 7.52-7.36(m, 3H), 7.36-7.26 (m, 1H), 6.47 (s, 1H), 6.36 (d, J=5.6 Hz, 1H),4.22-4.03 (m, 3H), 4.01-3.93 (m, 1H), 3.93-3.83 (m, 1H), 2.54-2.28 (m,5H), 1.54-1.33 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(4-(difluoromethoxy)naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-112)

The title compound is prepared using1-(difluoromethoxy)-4-iodonaphthalene in Step 2 instead of1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 536; ¹H NMR (400 MHz, MeOD)δ 8.56-8.47 (m, 1H), 8.30-8.23 (m, 1H), 8.20 (d, J=5.5 Hz, 1H), 7.78 (d,J=8.0 Hz, 1H), 7.69-7.56 (m, 2H), 7.33 (d, J=7.9 Hz, 1H), 7.09 (t,J=73.8 Hz, 1H), 6.69 (s, 1H), 6.38 (d, J=5.5 Hz, 1H), 4.26-4.08 (m, 3H),4.07-3.99 (m, 1H), 3.99-3.90 (m, 1H), 2.58-2.35 (m, 2H), 1.62-1.47 (m,1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(6-(difluoromethyl)naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-111)

The title compound is prepared using1-bromo-6-(difluoromethyl)naphthalene in Step 2 instead of1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 520; ¹H NMR (400 MHz, MeOD)δ 8.64 (d, J=8.9 Hz, 1H), 8.21 (d, J=5.5 Hz, 1H), 8.17-8.12 (m, 1H),8.06 (d, J=8.2 Hz, 1H), 7.95-7.87 (m, 1H), 7.73-7.63 (m, 2H), 6.94 (t,J=56.1 Hz, 1H), 6.73 (s, 1H), 6.40 (d, J=5.7 Hz, 1H), 4.29-4.07 (m, 3H),4.07-4.00 (m, 1H), 3.99-3.90 (m, 1H), 2.60-2.46 (m, 1H), 2.46-2.33 (m,1H), 1.63-1.48 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-methoxynaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate (I-104)

The title compound is prepared using 1-bromo-2-methoxynaphthalene inStep 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 500; ¹HNMR (400 MHz, MeOD) δ 8.20 (d, J=5.5 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H),7.91-7.77 (m, 1H), 7.72-7.56 (m, 1H), 7.50 (d, J=9.1 Hz, 1H), 7.40-7.23(m, 2H), 6.51 (s, 1H), 6.40-6.28 (m, 1H), 4.28-4.05 (m, 3H), 4.01-3.95(m, 1H), 3.95-3.89 (m, 1H), 3.87 (s, 3H), 2.59-2.45 (m, 1H), 2.45-2.35(m, 1H), 1.57-1.41 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(4-(dimethylamino)naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-107)

The title compound is prepared using1-bromo-4-(dimethylamino)naphthalene in Step 2 instead of1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 513; ¹H NMR (400 MHz, MeOD)δ 8.50-8.39 (m, 1H), 8.36-8.26 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 7.71 (d,J=7.8 Hz, 1H), 7.58-7.41 (m, 2H), 7.21 (d, J=7.8 Hz, 1H), 6.64 (s, 1H),6.37 (d, J=5.6 Hz, 1H), 4.28-4.08 (m, 3H), 4.07-3.99 (m, 1H), 3.99-3.91(m, 1H), 2.93 (s, 6H), 2.58-2.47 (m, 1H), 2.47-2.32 (m, 1H), 1.62-1.47(m, 1H).

(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(4-methoxynaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate (I-106)

The title compound is prepared using 1-iodo-4-methoxy-naphthalene inStep 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 500; ¹HNMR (400 MHz, MeOD) δ 8.49-8.39 (m, 1H), 8.35-8.26 (m, 1H), 8.17 (d,J=5.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.58-7.43 (m, 2H), 7.01 (d, J=8.0Hz, 1H), 6.64 (s, 1H), 6.35 (d, J=5.5 Hz, 1H), 4.26-4.08 (m, 3H), 4.06(s, 3H), 4.04-3.98 (m, 1H), 3.98-3.92 (m, 1H), 2.58-2.45 (m, 1H),2.45-2.32 (m, 1H), 1.60-1.45 (m, 1H).

(s.e.)-((1R,2R,3S,4R)-4-(2-(5-fluoronaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylsulfamate (I-105)

The title compound is prepared using 1-bromo-5-fluoronaphthalene in Step2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 488; ¹H NMR(400 MHz, MeOD) δ 8.30 (d, J=8.6 Hz, 1H), 8.24-8.16 (m, 2H), 7.93-7.84(m, 1H), 7.72-7.61 (m, 1H), 7.54-7.43 (m, 1H), 7.30-7.20 (m, 1H), 6.71(s, 1H), 6.40 (d, J=5.5 Hz, 1H), 4.27-4.08 (m, 3H), 4.07-3.99 (m, 1H),3.99-3.91 (m, 1H), 2.60-2.47 (m, 1H), 2.46-2.36 (m, 1H), 1.63-1.49 (m,1H).

(rac)-methylrel-5-[7-({(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoyloxy)methyl]-cyclopentyl}amino)pyrazolo[1,5-a]pyrimidin-2-yl]-2-naphthoate(I-96)

The title compound is prepared using methyl 5-bromo-2-naphthoate in Step2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+1 528; ¹H NMR(300 MHz, DMSO+D₂O) δ 8.72 (s, 1H), 8.62 (d, J=9.0 Hz, 1H), 8.30-8.16(m, 2H), 8.08-7.93 (m, 2H), 7.77-7.64 (m, 1H), 6.80 (s, 1H), 6.34 (d,J=5.5 Hz, 1H), 4.16-3.87 (m, 7H), 3.77-3.69 (m, 1H), 2.42-2.14 (m, 2H),1.56-1.41 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(5-fluoronaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-97)

The title compound is prepared using 1-bromo-5-fluoronaphthalene in Step2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+488; ¹H NMR (300MHz, DMSO) δ 8.32 (d, J=8.6 Hz, 1H), 8.27-8.11 (m, 2H), 7.93 (d, J=7.0Hz, 1H), 7.78-7.66 (m, 1H), 7.63-7.51 (m, 1H), 7.48-7.34 (m, 1H), 6.78(s, 1H), 6.34 (d, J=5.3 Hz, 1H), 4.19-4.07 (m, 1H), 4.07-3.92 (m, 3H),3.81-3.67 (m, 1H), 2.44-2.13 (m, 2H), 1.61-1.14 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(4-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-80)

The title compound is prepared using 4-bromophenyl trifluoromethylsulfide in Step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA)M+520; ¹H NMR (400 MHz, MeOD) δ 8.25-8.10 (m, 3H), 7.77 (d, J=8.3 Hz,2H), 6.86 (s, 1H), 6.35 (d, J=5.6 Hz, 1H), 4.30-4.18 (m, 2H), 4.17-4.08(m, 1H), 4.07-4.02 (m, 1H), 4.02-3.95 (m, 1H), 2.59-2.35 (m, 2H),1.67-1.53 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-79)

The title compound is prepared using 2-bromophenyltrifluoromethylsulfidein Step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+520; ¹HNMR (400 MHz, MeOD) δ 8.21 (d, J=5.8 Hz, 1H), 7.96-7.90 (m, 1H), 7.87(d, J=7.8 Hz, 1H), 7.69-7.62 (m, 1H), 7.60-7.51 (m, 1H), 6.76 (s, 1H),6.45 (d, J=5.9 Hz, 1H), 4.27-4.12 (m, 3H), 4.07-3.99 (m, 1H), 3.98-3.90(m, 1H), 2.57-2.33 (m, 2H), 1.66-1.52 (m, 1H).

(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(6-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate (I-64)

The title compound is prepared using 2-bromo-6-(trifluoromethyl)pyridinein Step 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+489; ¹HNMR (400 MHz, MeOD) δ 8.49 (d, J=8.0 Hz, 1H), 8.18 (d, J=5.5 Hz, 1H),8.15-8.07 (m, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.07 (s, 1H), 6.38 (d, J=5.6Hz, 1H), 4.32-4.18 (m, 2H), 4.18-4.09 (m, 1H), 4.08-3.94 (m, 2H),2.62-2.50 (m, 1H), 2.48-2.36 (m, 1H), 1.69-1.55 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(6-tert-butylpyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-52)

The title compound is prepared using 2-bromo-6-tert-butylpyridine inStep 2 instead of 1-chloro-4-iodo-naphthalene. LCMS: (AA) M+477; ¹H NMR(400 MHz, MeOD) δ 8.15 (d, J=5.5 Hz, 1H), 8.10-7.95 (m, 1H), 7.85-7.71(m, 1H), 7.48-7.35 (m, 1H), 7.03 (s, 1H), 6.34 (d, J=5.5 Hz, 1H),4.30-4.19 (m, 2H), 4.17-4.08 (m, 1H), 4.07-3.96 (m, 2H), 2.61-2.33 (m,2H), 1.71-1.52 (m, 1H), 1.43 (s, 9H).

(rac)-((1R,2R,3S,4R)-4-(2-(benzofuran-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-86)

The title compound is prepared using 2-iodo-1-benzofuran in Step 2instead of 1-chloro-4-iodo-naphthalene. LCMS: (FA) M+1 460.2; ¹H NMR(400 MHz, DMSO) δ 8.19 (d, J=5.3 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.73(d, J=7.1 Hz, 1H), 7.69-7.65 (m, 1H), 7.53-7.44 (m, 2H), 7.40-7.34 (m,1H), 7.34-7.26 (m, 1H), 6.93 (s, 1H), 6.32 (d, J=5.4 Hz, 1H), 5.04 (s,1H), 4.80 (s, 1H), 4.17-4.07 (m, 1H), 4.07-3.89 (m, 3H), 3.78 (s, 1H),2.40-2.13 (m, 2H), 1.58-1.44 (m, 1H).

Method C with Modification [Example 10]

Example 10. Synthesis of(rac)-[(1R,2R,3S,4R)-4-{[2-(3-cyclopentylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-48) Step 1:(rac)-rel-[(3aR,4R,6R,6aS)-6-{[2-(3-cyclopentylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol

(rac)-rel-[(3aR,4R,6R,6aS)-6-({2-[3-(cyclopent-1-en-1-yl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol(0.039 g, 0.087 mmol) is stirred in ethanol (2.3 mL, 39 mmol). Palladiumhydroxide (4.0 mg, 0.020 mmol) is added and the reaction is stirredunder a balloon of hydrogen overnight. The reaction mixture is filteredthrough celite, rinsed with ethanol and concentrated in vacuo to provide(rac)-rel-[(3aR,4R,6R,6aS)-6-{[2-(3-cyclopentylphenyl) pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol(39 mg, yield 100%). Used in the next step without purification.

Step 2:(rac)-[(1R,2R,3S,4R)-4-{[2-(3-cyclopentylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-48)

The title compound is synthesized from(rac)-rel-[(3aR,4R,6R,6aS)-6-{[2-(3-cyclopentylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanolfollowing Step 2 of Method A (yield 44%). LCMS: (AA) M+1 488; ¹H NMR(400 MHz, DMSO) δ 8.13 (d, J=5.3 Hz, 1H), 7.98-7.93 (m, 1H), 7.92-7.84(m, 1H), 7.72-7.59 (m, 1H), 7.53-7.43 (m, 2H), 7.42-7.34 (m, 1H),7.33-7.23 (m, 1H), 6.90 (s, 1H), 6.25 (d, J=5.4 Hz, 1H), 5.09-4.97 (m,1H), 4.87-4.75 (m, 1H), 4.19-4.09 (m, 1H), 4.08-3.99 (m, 1H), 4.00-3.90(m, 2H), 3.83-3.70 (m, 1H), 3.12-2.94 (m, 1H), 2.40-2.27 (m, 1H),2.28-2.15 (m, 1H), 2.13-1.98 (m, 2H), 1.88-1.74 (m, 2H), 1.74-1.54 (m,4H), 1.56-1.43 (m, 1H).

Method C with Modification [Example 11]

Example 11. Synthesis of(rac)-rel-5-[7-({(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl}amino)pyrazolo[1,5-a]pyrimidin-2-yl]-2-naphthoicacid (I-99)

To a solution of (rac)-methylrel-5-[7-({(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl}amino)pyrazolo[1,5-a]pyrimidin-2-yl]-2-naphthoate(0.048 g, 0.091 mmol) in DMF (2.0 mL, 26 mmol) is added 1.0 M NaOH (1.0mL, 1.0 mmol). The mixture is stirred at room temperature for 1.5 hr andthen concentrated in vacuo as an azeotropic mixture with toluene. Thecrude material is purified by preparative HPLC to provide(rac)-rel-5-[7-({(1R,2S,3R,4R)-2,3-dihydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl}amino)pyrazolo[1,5-a]pyrimidin-2-yl]-2-naphthoicacid (4.0 mg, yield 8.5%). LCMS: (AA) M+1 514; ¹H NMR (400 MHz, DMSO) δ8.71-8.63 (m, 1H), 8.55 (d, J=8.9 Hz, 1H), 8.25-8.16 (m, 2H), 8.09-7.98(m, 1H), 7.98-7.90 (m, 1H), 7.89-7.79 (m, 1H), 7.75-7.63 (m, 1H),7.55-7.25 (m, 1H), 6.79 (s, 1H), 6.33 (d, J=5.4 Hz, 1H), 5.2-4.6 (m,2H), 4.18-4.05 (m, 1H), 4.06-3.90 (m, 3H), 3.80-3.68 (m, 1H), 2.40-2.15(m, 2H), 1.56-1.36 (m, 1H).

Method C with Modification [Example 12]

Example 12. Synthesis of(rac)-[(1R,2R,3S,4R)-4-{[2-(3-ethynylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-83) Step 1:(rac)-rel-[(3aR,4R,6R,6aS)-6-{[2-(3-ethynylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol

(rac)-rel-{(3aR,4R,6R,6aS)-2,2-dimethyl-6-[(2-{3-[(trimethylsilyl)ethynyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(0.067 g, 0.00014 mol; synthesized following Step 1 in Method A exceptusing4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylethynyl-trimethylsilaneinstead of 1-naphthaleneboronic acid) is dissolved in methanol (0.03 mL,0.0007 mol). Potassium carbonate (21 mg, 0.00015 mol) is added and thesolution is stirred at room temperature overnight. The reaction mixtureis neutralized with saturated ammonium chloride solution and extractedwith dichlormethane. The organic layer is concentrated in vacuo andpurified by column chromatography (0-15% MeOH/CH₂Cl₂) to provide(rac)-rel-[(3aR,4R,6R,6aS)-6-{[2-(3-ethynylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol(0.046 g, yield 81%). LCMS: (AA) M+405; ¹H NMR (400 MHz, DMSO) δ8.25-8.05 (m, 4H), 7.52-7.44 (m, 2H), 7.00 (s, 1H), 6.25 (d, J=5.4 Hz,1H), 5.25-5.17 (m, 1H), 4.59-4.48 (m, 2H), 4.27 (s, 1H), 4.16-3.99 (m,1H), 3.65-3.44 (m, 2H), 2.48-2.38 (m, 1H), 2.28-2.19 (m, 1H), 1.87-1.72(m, 1H), 1.46 (s, 3H), 1.24 (s, 3H).

Step 2:(rac)-[(1R,2R,3S,4R)-4-{[2-(3-ethynylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-83)

The title compound is synthesized from(rac)-rel-[(3aR,4R,6R,6aS)-6-{[2-(3-ethynylphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanolfollowing Step 2 of Method A. LCMS: (AA) M+444; ¹H NMR (400 MHz, MeOD) δ8.22-8.16 (m, 1H), 8.13 (d, J=5.5 Hz, 1H), 8.07-7.99 (m, 1H), 7.55-7.34(m, 2H), 6.78 (s, 1H), 6.32 (d, J=5.6 Hz, 1H), 4.28-4.17 (m, 2H),4.16-4.07 (m, 1H), 4.07-4.02 (m, 1H), 4.01-3.94 (m, 1H), 3.55 (s, 1H),2.60-2.29 (m, 2H), 1.67-1.47 (m, 1H).

Example 13. Compounds prepared by Method D(rac)-{(1R,2R,3S,4R)-4-[(5-chloro-2-phenylpyrazo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methylrel-sulfamate (I-6)

The title compound is prepared using 5-amino-3-phenylpyrazole in Step 1instead of 3-(1-naphthyl)-1H-pyrazol-5-amine. LCMS: (AA) M+1 454; ¹H NMR(400 MHz, MeOD) δ 8.03 (d, J=8.5 Hz, 2H), 7.45 (t, J=7.3 Hz, 2H), 7.39(t, J=7.3 Hz, 1H), 6.72 (s, 1H), 6.36 (s, 1H), 4.28-4.17 (m, 2H),4.13-3.94 (m, 3H), 2.55-2.36 (m, 2H), 1.67-1.54 (m, 1H).

(rac)-[(1R,2R,3S,4R)-4-{[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (I-14)

The title compound is prepared using 5-amino-3-(4-methoxyphenyl)pyrazolein Step 1 instead of 3-(1-naphthyl)-1H-pyrazol-5-amine. LCMS: (AA) M+1484; ¹H NMR (300 MHz, MeOD) δ 7.94 (d, J=8.9 Hz, 2H), 7.00 (dd, J=9.3,2.4 Hz, 2H), 6.62 (s, 1H), 6.32 (s, 1H), 4.29-4.16 (m, 2H), 4.12-3.93(m, 3H), 3.84 (s, 3H), 2.57-2.33 (m, 2H), 1.66-1.52 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(2-(4-bromophenyl)-5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-8)

The title compound is prepared using5-(4-bromophenyl)-2H-pyrazol-3-ylamine in Step 1 instead of3-(1-naphthyl)-1H-pyrazol-5-amine. LCMS: (AA) M+1 532; ¹H NMR (300 MHz,DMSO) δ 8.04 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H), 6.95 (s, 1H),6.35 (s, 1H), 4.16-3.88 (m, 4H), 3.79-3.68 (m, 1H), 2.33-2.17 (m, 2H),1.61-1.37 (m, 1H).

(rac)-((1R,2R,3S,4R)-4-(5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate (I-11)

The title compound is prepared using 5-pyridin-2-yl-2H-pyrazol-3-ylaminein Step 1 instead of 3-(1-naphthyl)-1H-pyrazol-5-amine. LCMS: (AA) M+1455; ¹H NMR (400 MHz, MeOD) δ 8.64 (d, J=4.9 Hz, 1H), 8.23 (d, J=7.9 Hz,1H), 8.01-7.85 (m, 1H), 7.48-7.36 (m, 1H), 6.95 (s, 1H), 6.41 (s, 1H),4.30-4.18 (m, 2H), 4.14-3.93 (m, 3H), 2.60-2.35 (m, 2H), 1.68-1.54 (m,1H).

Method D with Modification [Example 14]

Example 14.(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methylrel-sulfamate (I-12)

(rac)-[(1R,2R,3S,4R)-4-{[5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (5.0 mg, 0.011 mmol; synthesized following Steps 1-4 ofMethod D starting from 5-pyridin-2-yl-2H-pyrazol-3-ylamine) is dissolvedin methanol (1.00 mL, 0.0247 mol). Palladium on carbon (10%, 29.2 mg,0.00275 mmol) is added and the suspension is purged with hydrogen gasand stirred for 3 days at room temperature under a balloon of hydrogen(1 atm). The reaction mixture is purged with nitrogen, filtered throughcelite and rinsed with methanol. The filtrate is concentrated in vacuoand purified by preparative HPLC to provide(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methylrel-sulfamate (1.0 mg, yield 22%). LCMS: (AA) M+1 421; ¹H NMR (400 MHz,MeOD) δ 8.72-8.61 (m, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.18 (d, J=4.8 Hz,1H), 7.99-7.88 (m, 1H), 7.47-7.37 (m, 1H), 7.01 (s, 1H), 6.41-6.32 (m,1H), 4.30-4.18 (m, 2H), 4.16-3.92 (m, 3H), 2.61-2.49 (m, 1H), 2.48-2.35(m, 1H), 1.68-1.56 (m, 1H).

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(4-phenyl-1,3-thiazol-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl]methylrel-sulfamate (I-31)

The title compound is prepared following Method D with Modificationstarting from(rac)-[(1R,2R,3S,4R)-4-{[5-chloro-2-(4-phenyl-1,3-thiazol-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate (synthesized following Steps 1-4 of Method D starting from3-(4-phenylthiazol-2-yl)-1H-pyrazol-5-amine). LCMS: (AA) M+1 503; ¹H NMR(400 MHz, MeOD) δ 8.20 (d, J=5.5 Hz, 1H), 8.06-7.99 (m, 2H), 7.90 (s,1H), 7.46 (t, J=7.8 Hz, 2H), 7.37 (t, J=7.4 Hz, 1H), 7.02 (s, 1H), 6.42(d, J=5.5 Hz, 1H), 4.30-4.10 (m, 3H), 4.06 (t, J=5.9 Hz, 1H), 3.99 (t,J=5.3 Hz, 1H), 2.58-2.48 (m, 1H), 2.48-2.37 (m, 1H), 1.67-1.56 (m, 1H).

Method G [Example 15]

Example 15. Synthesis of(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(6-phenylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylrel-sulfamate (I-121)

Step 1. (rac)-(1S,2R,3R,5R)-3-(hydroxymethyl)-5-{[2-(6-phenylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentane-1,2-diyl dibenzoate. The title compound is prepared starting from(rac)-(1R,2S,3R,5R)-3-{[5-chloro-2-(6-phenylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-5-(hydroxymethyl)cyclopentane-1,2-diyldibenzoate (prepared from 3-(6-phenylpyrazin-2-yl)-1H-pyrazol-5-aminefollowing Steps 1-3 of Method D) following Step 5 of Method F.

Step 2.(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(6-phenylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methylsulfamate (I-121). The title compound is prepared from(rac)-(1S,2R,3R,5R)-3-(hydroxymethyl)-5-{[2-(6-phenylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentane-1,2-diyl dibenzoate following Step 7 of Method B. LCMS: (AA) M+1 498; ¹HNMR (400 MHz, DMSO) δ 8.32-8.27 (m, 2H), 8.22 (d, J=5.3 Hz, 1H), 7.87(s, 1H), 7.63-7.52 (m, 4H), 7.16 (s, 1H), 6.37 (d, J=5.4 Hz, 1H), 5.08(s, 1H), 4.86 (s, 1H), 4.19-4.11 (m, 1H), 4.08-3.95 (m, 3H), 3.84-3.74(m, 1H), 2.42-2.19 (m, 2H), 1.59-1.47 (m, 1H).

Also prepared by Method G:

(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-({2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclopentyl]methyl rel-sulfamate (I-122)

The title compound is prepared using(rac)-(1S,2R,3R,5R)-3-(hydroxymethyl)-5-({2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)cyclopentane-1,2-diyldibenzoate in Step 1 instead of(rac)-(1R,2S,3R,5R)-3-{[5-chloro-2-(6-phenylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-5-(hydroxymethyl)cyclopentane-1,2-diyldibenzoate. LCMS: (AA) M+1 500; ¹H NMR (400 MHz, DMSO) δ 8.23 (s, 2H),8.15 (d, J=5.3 Hz, 1H), 7.97 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.65 (s,1H), 7.61-7.57 (m, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.00 (s, 1H), 6.27 (d,J=5.4 Hz, 1H), 4.17-4.10 (m, 1H), 4.07-3.93 (m, 3H), 3.89 (s, 3H),3.80-3.75 (m, 1H), 2.41-2.19 (m, 2H), 1.57-1.45 (m, 1H).

Example 16. Synthesis of(rac)-{(1R,2R,3S,4R)-4-[(2-{3-[2-chloro-1-(hydroxymethyl)-1-methylethyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methyl rel-sulfamate(I-123)

Step 1

The title compound is prepared from(rac)-[(3aR,4R,6R,6aS)-2,2-dimethyl-6-({2-[3-(3-methyloxetan-3-yl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanolfollowing Step 2 in Method A and adding 5 equivalents of pyridiniump-toluenesulfonate after the addition of hydrochloric acid. LCMS: (AA)M+1 526.

Example 17. Synthesis of(s.e.)-{(1R,2R,3S,4R)-4-[(3,6-dichloro-2-{3-[(trifluoromethyl)sulfanyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (I-124) and(s.e.)-{(1R,2R,3S,4R)-4-[(6-chloro-2-{3-[(trifluoromethyl)sulfanyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (I-125)

Step 1

To a vial containing(s.e.)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(2-{3-[(trifluoromethyl)sulfanyl]phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl}methylsulfamate (0.82 g, 0.0015 mol) and cooled to 0° C. is addedN-chlorosuccinimide (126 mg, 0.000943 mol) as a solution in 12 mL ofN,N-dimethylformamide. The reaction mixture is stirred overnight withwarming to rt. Saturated sodium bicarbonate solution is added and thereaction mixture is extracted with ethyl acetate, washed with brine,dried over sodium sulfate and concentrated in vacuo. The crude materialis first purified by column chromatography (eluent: methanol/methylenechloride) and then purified by HPLC to afford both the dichloro (LCMS:(FA) M+1 588) and mono chloro (LCMS: (FA) M+1 554) title compounds.

Example 18.(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate (I-101)

The title compound is prepared following Example 2a with any of thefollowing modifications to Step 2: (I) After the addition of 6 Mhydrochloric acid in water and stirring for 1 hr, the reaction mixtureis made basic by the addition of a 1.0 M sodium hydroxide solution.Solvent is removed in vacuo and methanol is added to the crude residue.The resulting suspension is filtered through syringe filter to removeinorganic salts and then concentrated in vacuo. The crude material ispurified by either HPLC or column chromatography (eluent: methylenechloride/methanol). (II) After the addition of 6 M hydrochloric acid inwater and stirring for 1 hr, the reaction mixture is made basic by theaddition of a 1.0 M sodium hydroxide solution. Solvent is removed invacuo and methanol is added to the crude residue. The resultingsuspension is filtered through syringe filter to remove inorganic saltsand then concentrated in vacuo. The crude material is purified by eitherHPLC or column chromatography (eluent: methylene chloride/methanol).(III) Water:tetrahydrofuran (2.6:1) is used as the solvent instead ofN,N-dimethylformamide. 12 M hydrochloric acid in water is used insteadof 6 M hydrochloric acid in water. Upon completion, solid sodiumbicarbonate is added to neutralize the reaction mixture. The mixture isdiluted with water and concentrated in vacuo to remove the THF duringwhich time a precipitate is formed. The mixture is stirred for 30minutes and the precipitate is collected by vacuum filtration and driedunder vacuum. NMR and LCMS data correspond to data previously describedfor I-101.

Example 19.(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 1 anhydrous Step 1: Synthesis oftert-butyl-[({(3aR,4R,6aS)-2,2-dimethyl-6-[(2-{3-(trifluoromethylthio)phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methoxy)sulfonyl]carbamate

{(3aR,4R,6R,6aS)-2,2-dimethyl-6-[(2-{3-(trifluoromethylthio)phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(3.4 g) was dissolved in 2-methyltetrahedrafuran (32.0 mL) and to thissolution was added pyridinium p-toluenesulfonate (3.34 g). This formed aprecipitate and to this white slurry was added(4-aza-1-azoniabicyclo[2.2.2]oct-1-ylsulfonyl)(tert-butoxycarbonyl)azanide-1,4-diazabicyclo[2.2.2]octane (1:1)hydrochloride (8.19 g). (prepared according to Armitage, I. et. al. U.S.Patent Application Publication US2009/0036678, and Armitage, I. et. al.Org. Lett., 2012, 14 (10), 2626-2629). The mixture was stirred atambient temperature until the HPLC showed <1% remaining startingmaterial (about 300 minutes). To the reaction was added ethyl acetate(30 mL) and water (30 mL). After stirring for 10 minutes the phases wereseparated and the aqueous layer was back extracted with ethyl acetate(30 mL). The organic layers were combined and washed with 10% brine (30mL) and the layers were separated. The organic layer was thenconcentrated to dryness to give an off-white solid. The solids weretransferred back to the reactor with acetonitrile (35 m L) and stirredfor 20 minutes. The solids were isolated by filtration and dried in avacuum oven at full vacuum overnight (40° C., 16 hours) to givetert-butyl-[({(3aR,4R,6aS)-2,2-dimethyl-6-[(2-{3-(trifluoromethylthio)phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methoxy)sulfonyl]carbamate(3.87 g, 88%). (LCMS: (FA2) M+1 660).

Step 2:(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 1 anhydrous

To a solution oftert-butyl-[({(3aR,4R,6aS)-2,2-dimethyl-6-[(2-{3-(trifluoromethylthio)phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methoxy)sulfonyl]carbamate(4.0 g) in acetonitrile (20.0 mL) at 0° C. was added phosphoric acid(20.0 mL) while maintaining the temperature below 10° C. This mixturewas warmed to ambient temperature and stirred for 4 hours. At this timeHPLC analysis showed that <1% starting material or reactionintermediates remained. To the reaction was added ethyl acetate (20 mL)and water (20 mL). After this addition was complete saturated Na₂CO₃(80.0 mL) was added until the pH was between 6-7. After stirring for 10minutes the phases were separated and the aqueous layer was backextracted with ethyl acetate (20 mL). The organic layers were combinedand dried with Na₂SO₄. The organic layer was then concentrated to 4 volof ethyl acetate. The solution started to precipitate within 5 minutes.This mixture was stirred for 16 hours. The resulting white solids werecollected using a filter over 5 minutes. The solid was dried in a vacuumoven under full vacuum overnight (35° C., 16 hours). This yielded(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate anhydrous Form 1. (2.85 g, 84%). XRPD data is shown in FIG. 1;DSC data is shown in FIG. 2; TGA is shown in FIG. 3; Raman data is shownin FIGS. 4, 5A, 6A and 7A.

Form 1 can also be prepared in the following way:

To a solution oftert-butyl-[({(3aR,4R,6aS)-2,2-dimethyl-6-[(2-{3-(trifluoromethylthio)phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methoxy)sulfonyl]carbamate(2.4 g) in acetonitrile (12.0 mL) at 0° C. was added phosphoric acid(12.0 mL) while maintaining the temperature below 10° C. This mixturewas warmed to ambient temperature and stirred for 4 hours. At this timeHPLC analysis showed that <1% starting material or reactionintermediates remained. To the reaction was added ethyl acetate (12 mL)and water (12 mL). After this addition was complete saturated Na₂CO₃(48.0 mL) was added until the pH was between 6-7. After stirring for 10minutes the phases were separated and the aqueous layer was backextracted with ethyl acetate (20 mL). The combined organic layers werethen washed with water (24 mL). To the organic layer was then addedacetonitrile (24 mL) and it was then concentrated to ˜10 volumes. To theorganic layer was then added acetonitrile (24 mL) and it wasconcentrated to ˜10 volumes. To the organic layer was then addedacetonitrile (24 mL) and it was concentrated to ˜5 vol of acetonitrile.(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 1 anhydrous (prepared in Step 2 above). The solutionstarted to precipitate within 5 minutes. This mixture was stirred for 16hours. The resulting white solids were collected using a filter over 5minutes. The solid was dried in a vacuum oven under full vacuumovernight (35° C., 16 hours). This yielded(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 1 anhydrous (1.35 g, 71%). The analytical data isconsistent with Form 1.

Form 1 can also be prepared in the following way:

To(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 1 anhydrous (5.0 g) was added acetonitrile (32 mL) andwater (8 mL). This mixture was heated to 50° C. at which point all thesolids were in solution. To this solution was added water (40 mL) whilemaintaining the solution temperature at 50° C. The solution was thenseeded with(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 1 anhydrous (prepared in Step 2 above). The seed did notdissolve and the mixture was then cooled over 12 hours to 22° C. Theresulting white solids were collected using a filter over 5 minutes. Thesolid was dried in a vacuum oven under full vacuum overnight (35° C., 16hours) to yield(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 1 anhydrous (4.25 g, 85%). The analytical data isconsistent with Form 1.

Example 20.(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 2 monohydrated

To a solution oftert-butyl-[({(3aR,4R,6aS)-2,2-dimethyl-6-[(2-{3-(trifluoromethylthio)phenyl}pyrazolo[1,5-a]pyrimidin-7-yl)amino]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methoxy)sulfonyl]carbamate(5.0 g) in acetonitrile (25.0 mL) at 0° C. was added phosphoric acid(25.0 mL) while maintaining the temperature below 10° C. This mixturewas warmed to ambient temperature and stirred for 4 hours. At this timeHPLC analysis showed that <1% starting material or reactionintermediates remained. To the reaction was added ethyl acetate (25 mL)and water (25 mL). After this addition was complete saturated Na₂CO₃(100.0 mL) was added until the pH was between 6-7. After stirring for 10minutes the phases were separated and the aqueous layer was backextracted with ethyl acetate (25 mL). The combine organics were thenwashed with 10% brine (50 mL). The organic layers were dried withNa₂SO₄. The organic layer was then concentrated to 4 vol of ethylacetate. The solution started to precipitate within 5 minutes. Thismixture was stirred for 16 hours. The resulting white solids werecollected using a filter over 5 minutes. The solid was dried in a vacuumoven under full vacuum overnight (35° C., 16 hours). This yielded(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 2 monohydrated (3.04 g, 77%). XRPD data is shown in FIG.8; DSC data is shown in FIG. 9; TGA is shown in FIG. 10; Raman data isshown in FIGS. 11, 5B, 6B and 7B.

Form 2 can also be prepared in the following way:

(s.e.)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 1 anhydrous (1.5 g) dissolved in 90:10/MeCN:water (25.0mL) at 50° C. The solution was rapidly cooled to 5° C. To the solutionwas added water (20 mL) while maintaining the temperature. The reactionwas then seeded with(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 2 monohydrated (prepared as above). The solution wasstirred for 2 hours at 5° C. and the solution remained cloudy.Additional water (11.25 mL) was then added and the mixture was stirredfor 16 hours. The slurry was then filtered and dried for 48 hours. Thisgave(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 2 monohydrated (1.21 g, 95%) The analytical data isconsistent with Form 2.

Example 21. Competitive Slurrying Experiments

Approximately 10 mg of a 1:1 mixture of(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 1 anhydrous and(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate Form 2 monohydrated was placed in a vial and 100 μl of thesolvents listed below in Table 5 (which had been previously saturated inForm 1) were added to the vial. The vials were agitated at thetemperature shown below for 60 hours. Any solids remaining at this pointwere isolated by centrifugation and analysed by XRPD.

TABLE 5 Summary of Competitive Slurrying Experiments Temperature SolventComposition Form present by (° C.) % MeCN % Water XRPD analysis 5 90 10Form 2 5 80 20 Form 2 5 70 30 Form 2 ambient 90 10 Mixture ambient 80 20Mixture ambient 70 30 Mixture 50 90 10 Form 1 50 80 20 Form 1 50 70 30Form 1

In all the solvent systems studied Form 2 was isolated at 5° C. and Form1 was isolated at 50° C. showing that isolation of the desired form canbe controlled with temperature.

Example 22. Preparation of(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate solution for parenteral administration

The composition of the formulation of(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate for injection (intravenous or subcutaneous) is shown in Table6

TABLE 6 Quantitative composition of sterile solution for parenteraladministration Amount Component Function (mg/mL) Citric Acid anhydrous,USP Excipient 9.61 β-Cyclodextrin Sulfobutyl Ethers, Sodium Excipient 50Salts (Captisol ®) (Ligand Pharmaceuticals Inc)(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2- 2(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate Form 1 anhydrousSodium Hydroxide pH adjuster q.s. to pH 3.3 ± 0.5 Water for InjectionSolvent q.s. to 1 mL

A batch of(s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)-phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylsulfamate sterile solution for parenteral administration is prepared byperforming the following steps:

-   -   1) Calculate the required amount of excipients and solvent per        lot using the quantitative composition of the formulation shown        in Table 3.    -   2) Add the calculated amount of anhydrous citric acid to 75% of        the calculated amount of sterile Water for Injection and stir        until citric acid is completely dissolved.    -   3) Add the calculated amount of Captisol® to the solution and        stir until Captisol® is completely dissolved.    -   4) Add the calculated amount of        (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl        sulfamate Form 1 anhydrous to the solution and stir until        completely dissolved.    -   5) Adjust the pH of the solution to a target of 3.3±0.5 using        sodium hydroxide solution.    -   6) Adjust the volume of the solution to a target of 2.0 mg/mL        (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl        sulfamate concentration using sterile Water for Injection.    -   7) Filter the compounded bulk solution using a 0.45 μM        clarifying filter followed by a 0.2 μM sterilizing filter for        bio-burden reduction and sterilization, respectively.    -   8) Aseptically fill the sterile solution in sterile and        depyrogenated vials.    -   9) Seal the filled vials are using sterile rubber stoppers and        overseal using sterile aluminum crimps with polypropylene caps.

Biological Assays Ubiquitin Activating Enzyme (UAE) HTRF Assay

The UAE enzymatic reaction totals 50 μL and contains 50 mmol HEPES (pH7.5), 0.05% BSA, 2.5 mM MgCl2, 0.1 uM ATP, 8 nM GST-Ubc-2, 35 nMflag-ubiquitin, 1 nM recombinant human UAE or mouse UAE. Compounds forthis hUAE IC50 assay are tested at 10 point 3-fold dilution. The topconcentration for this assay is 1 μM. Each compound is ordered induplicate on the same plate. The enzymatic reaction mixture is incubatedfor 90 minutes at room temperature (24 degrees C.) in a 384 well plateprior to termination with a stop solution (0.1 M HEPES/0.05% Tween20, 20mmol EDTA, 410 mM KF, 0.5 nM Eu Cryptate anti-FLAG M2-K antibody(Cis-bio International), 8 ug/mL Anti-GST XL-APC (Prozyme)). Afterincubation for 120 minutes, quantification of the FRET is performed onthe Pherostar (BMG).

From the Pherastar rawdata files, % inhibition vs. plate based controlsis calculated. Dose response data is further processed in GenedataCondoseo, which performs as 4 parameter logistic fit and determines theIC₅₀ (intercept at 50% inhibition) for each compound. The results areshown in the following table. For compounds whose values are marked withan asterisk (*), mouse UAE was used. For all other compounds, human UAEwas used.

% inhibition Compound no. Example no. @0.111 μM IC₅₀ ^(†) I-001 8  72* BI-002  2b  100* A I-003 8 100 A I-004 5  31 C I-005 8  100* A I-006 13  23 C I-007 8  99 A I-008 13   28 C I-009 4  42 C I-010 7 100 A I-01113   49* C I-012 14   61* B I-013 8  84 B I-014 13   30 C I-015 8 100 AI-016 7  99 A I-017 7 100 A I-018 7 100 A I-019 7 100 A I-020 7 100 AI-021 7  97 A I-022 7 100 A I-023 7  96 B I-024 7  98 A I-025 7  93 BI-026 7 100 A I-027 7 100 A I-028 7  99 A I-029 7 100 A I-030 7  99 AI-031 14  100 A I-032 7 100 A I-033 7  98 A I-034 7 100 A I-035 7 100 AI-036 7 100 A I-037 7 100 A I-038 7 100 A I-039 7 100 A I-040 7 100 AI-041 7  99 A I-042 7 100 A I-043 7 100 A I-044 7 100 A I-045 7 100 AI-046 7 100 A I-047 9 100 A I-048 10  100 A I-049 7 100 A I-050 7 100 AI-051 7  90 B I-052 9 100 A I-053 7 100 A I-054 7 100 A I-055 7 100 AI-056 7 100 A I-057 7 100 A I-058 9 100 A I-059 7  94 B I-060 7  89 BI-061 7 100 A I-062 7 100 A I-063 9 100 A I-064 9  96 B I-065 7 100 AI-066 7 100 A I-067 7 100 A I-068 7  95 B I-069 7  84 B I-070 7  99 AI-071 7 100 A I-072 7 100 A I-073 7  91 B I-074 7  98 B I-075 7 100 AI-076 7 100 A I-077 7 100 A I-078 7 100 A I-079 9  75 B I-080 9  80 BI-081 7 100 A I-082 7 100 A I-083 12  100 A I-084 7 100 A I-085 9  99 AI-086 9  99 A I-087 7 100 A I-088 7  97 B I-089 6  27 C I-090 7 100 AI-091 7  100* A I-092 7 100 A I-093 9 100 A I-094 7 100 A I-095 7  70 BI-096 9 100 A I-097 9 100 A I-098  2a 100 A I-099 11  100 A I-100 7 100A I-101 7  99 A I-102 7 100 A I-103 7 100 A I-104 9 100 A I-105 9 100 AI-106 9 100 A I-107 9 100 A I-108 3 100 A I-109 9 100 A I-110 9 100 AI-111 9 100 A I-112 9 100 A I-113 7 100 A I-114 9  99 A I-115 9 100 AI-116 7 100 A I-117 7  92 B I-118 7 100 A I-119 7  99 A I-120 7 100 AI-121 15  100 A I-122 15   97 A I-123 16  100 A I-124 17   20 C I-12517   50 C ^(†) A means IC₅₀ < 10 nM B means 10 nM ≦ IC₅₀ < 100 nM Cmeans 100 nM ≦ IC₅₀ < 1 μM

While a number of embodiments of this invention have been described, itis apparent that the provided examples may be altered to convey otherembodiments, which utilize the chemical entities and methods of thisinvention. It will thus be appreciated that the scope of this inventionhas been represented herein by way of example and is not intended to belimited by the specific embodiments described.

1. A chemical entity comprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: W is—N(R^(*3))—; Y is

each of R^(Y1), R^(Y2) and R^(Y3) is independently selected from —H, (a)halo, (b1) C₁₋₃ aliphatic, (b2) R^(#2-1), (c) —OR^(*3), (d) —N(R^(*3))₂,(e) —SR^(†3), (f) C₁₋₂ haloalkyl and (g) C₁₋₂ haloalkoxy; Z is (1)optionally substituted fused aryl:

 wherein

 represents the aryl group, and

 represents the carbocycle or heterocycle; or (2)

 wherein X⁴ is —O—, —N(R^(*3))—, —S— or —C(O)—; and each of n1 and n2 isindependently 0, 1 or 2, provided that n1+n2=0, 1 or 2; each instance ofR^(S1) is independently selected from —H, (a) halo, (c) —OR^(*2), (d)—N(R^(*2))₂ and (e) —SR^(†2); each instance of R^(S2) is independentlyselected from —H, (a) halo, (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4),(h) —NO₂, (i) —CN, (j) —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l)—C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)—O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and(r) —N(R^(*4))—C(O)—N(R^(*4))₂; each instance of R^(S4) is independentlyselected from —H, (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c)—OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4); each instance of R^(S5) isindependently selected from —H, (a) halo, (b1) C₁₋₄ aliphatic, (b2)R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f) C₁₋₃haloalkyl, (h) —NO₂, (i) —CN, (j) —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l)—C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o)—O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and(r) —N(R^(*4))—C(O)—N(R^(*4))₂; each instance of R^(S7) is independentlyselected from —H, (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c)—OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4); each instance of R^(S8) isindependently selected from —H, (a) halo, (b1) C₁₋₄ aliphatic, (b2)R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f) C₁₋₃haloalkyl, (g1) C₁₋₃ haloalkoxy, (g2) C₁₋₃ haloalkylthio, (h) —NO₂, (i)—CN, (j) —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)—O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o) —O—C(O)—OR^(*4), (p)—O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and (r)—N(R^(*4))—C(O)—N(R^(*4))₂; each instance of R^(S9) is independentlyselected from —H, (a) halo, (b1) C₁₋₆ aliphatic, (b2) R^(̂6-3), (c)—OR^(*6), (d) —N(R^(*6))₂, (e) —SR^(†6), (f) C₁₋₃ haloalkyl, (g1) C₁₋₃haloalkoxy, (g2) C₁₋₃ haloalkylthio, (h) —NO₂, (i) —CN, (j)—C(O)—R^(†6), (k) —C(O)—OR^(*6), (l) —C(O)—N(R^(*6))₂, (m)—O—C(O)—R^(†6), (n) —N(R^(*6))—C(O)—R^(†6), (o) —O—C(O)—OR^(*6), (p)—O—C(O)—N(R^(*6))₂, (q) —N(R^(*6))—C(O)—OR^(*6), (r)—N(R^(*6))—C(O)—N(R^(*6))₂, (s) —Si(R^(†2))₃, (aa) C₃₋₈ carbocyclyl,(bb) -A-(C₃₋₈ carbocyclyl), (cc) 5- to 10-membered heterocyclyl, (dd)-A-(5- to 10-membered heterocyclyl), (ee) C₆₋₁₀ aryl, (ff) -A-(C₆₋₁₀aryl), (gg) 5- to 10-membered heteroaryl and (hh) -A-(5- to 10-memberedheteroaryl); wherein each instance of A is independently selected fromC₁₋₃ alkylene, C_(0-3,0-3) heteroalkylene, —O—, —S—, —N(R^(*1))— and—C(O)—; and wherein each of (aa)-(dd) is optionally substituted with 1-3groups independently selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2)R^(#2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); and whereineach of (ee)-(hh) is optionally substituted with 1-3 groupsindependently selected from (a) halo, (b1) C₁₋₄ aliphatic, (b2)R^(#4-2), (c) —OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4); each instanceof R^(*6) is independently —H or C₁₋₆ alkyl; each instance of R^(*4) isindependently —H or C₁₋₄ alkyl; each instance of R^(*3) is independently—H or C₁₋₃ alkyl; each instance of R^(*2) is independently —H or C₁₋₂alkyl; each instance of R^(*1) is independently —H or methyl; eachinstance of R^(†6) is independently C₁₋₆ alkyl; each instance of R^(†4)is independently C₁₋₄ alkyl; each instance of R^(†3) is independentlyC₁₋₃ alkyl; each instance of R^(†2) is independently C₁₋₂ alkyl; eachinstance of R^(̂6-3) is independently

wherein

represents C₁₋₆ alkyl; and each of m1, m2 and m3 is independently 0 or1; each instance of R^(̂4-2) is independently

wherein

represents C₁₋₄ alkyl; and each of m1 and m2 is independently 0 or 1;each instance of R^(#4-2) is independently

wherein

represents C₁₋₄ alkyl; and each of m1 and m2 is independently 0 or 1;and each instance of R^(#2-1) is independently

wherein

represents C₁₋₂ alkyl; and m1 is 0 or
 1. 2. The chemical entity of claim1, wherein W is —NH—.
 3. The chemical entity of claim 1, wherein each ofR^(Y1), R^(Y2) and R^(Y3) is independently selected from —H, (a) haloand (b1) C₁₋₃ alkyl.
 4. The chemical entity of claim 3, wherein each ofR^(Y1), R^(Y2), and R^(Y3) is —H. 5.-23. (canceled)
 24. The chemicalentity of claim 1, wherein Z is optionally substituted fused aryl:

wherein

represents the aryl group, and

 represents the carbocycle or heterocycle; R^(S4.2) is selected from —H,(a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(#4-2), (c) —OR^(*4), (d)—N(R^(*4))₂ and (e) —SR^(†4); R^(S5.2) is selected from —H, (a) halo,(b1) C₁₋₄ aliphatic, (b2) R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e)—SR^(†4), (f) C₁₋₃ haloalkyl, (h) —NO₂, (i) —CN, (j) —C(O)—R^(†4), (k)—C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n)—N(R^(*4))—C(O)—R^(†4), (o) —O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q)—N(R^(*4))—C(O)—OR^(*4) and (r) —N(R^(*4))—C(O)—N(R^(*4))₂; R^(S8.2) isselected from —H, (a) halo, (b1) C₁₋₄ aliphatic, (b2) R^(̂4-2), (c)—OR^(*4), (d) —N(R^(*4))₂, (e) —SR^(†4), (f) C₁₋₃ haloalkyl, (g) C₁₋₃haloalkoxy, (h) —NO₂, (i) —CN, (j) —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l)—C(O)—N(R^(*4))₂, (m) —O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R⁴, (o)—O—C(O)—OR^(*4), (p) —O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and(r) —N(R^(*4))—C(O)—N(R^(*4))₂; R^(S9.2) is selected from —H, (a) halo,(b1) C₁₋₄ aliphatic, (b2) R^(̂4-2), (c) —OR^(*4), (d) —N(R^(*4))₂, (e)—SR^(†4), (f) C₁₋₃ haloalkyl, (g) C₁₋₃ haloalkoxy, (h) —NO₂, (i) —CN,(j) —C(O)—R^(†4), (k) —C(O)—OR^(*4), (l) —C(O)—N(R^(*4))₂, (m)—O—C(O)—R^(†4), (n) —N(R^(*4))—C(O)—R^(†4), (o) —O—C(O)—OR^(*4), (p)—O—C(O)—N(R^(*4))₂, (q) —N(R^(*4))—C(O)—OR^(*4) and (r)—N(R^(*4))—C(O)—N(R^(*4))₂, (aa) C₃₋₆ carbocyclyl, (cc) 5- to 6-memberedheterocyclyl, (ee) C₆ aryl and (gg) 5- to 6-membered heteroaryl; whereineach of (aa) and (cc) is optionally substituted with 1-2 groupsindependently selected from (a) halo, (b1) C₁₋₂ aliphatic, (b2)R^(#2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); and whereineach of (ee) and (gg) is optionally substituted with 1-3 groupsindependently selected from (a) halo, (b1) C₁₋₄ aliphatic, (b2)R^(#4-2), (c) —OR^(*4), (d) —N(R^(*4))₂ and (e) —SR^(†4).
 25. Thechemical entity of claim 24, wherein: the aryl group is a C₆ aryl group;the carbocycle is a C₅₋₆ carbocycle; and the heterocycle is a 5- to6-membered heterocycle having one ring heteroatom selected from —O—,—N(R^(*1))— and —S—.
 26. The chemical entity of claim 24, wherein Z isoptionally substituted indanyl, 2,3-dihydrobenzofuranyl or1,3-dihydroisobenzofuranyl.
 27. The chemical entity of claim 24,wherein: R^(S4.2) is selected from —H, (a) —F, Cl, (b1) C₁₋₂ aliphatic,(b2) R^(̂2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e) —SR^(†2); R^(S5.2)is selected from —H, (a) halo, (b1) C₁₋₂ aliphatic, (b2) R^(̂2-1), (c)—OR^(*2), (d) —N(R^(*2))₂, (e) —SR^(†2) and (f) —CF₃; R^(S8.2) is —H;and R^(S9.2) is selected from —H, (a) —F, Cl, (b1) C₁₋₂ aliphatic, (b2)R^(̂2-1), (c) —OR^(*2), (d) —N(R^(*2))₂, (e) —SR^(†2), (f) —CF₃ and (g)—OCF₃.
 28. The chemical entity of claim 24, wherein the compound isI-023(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate; I-026(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate; I-041(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate; or I-053(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-1,3-dihydroisobenzofuran-5-yl)pyrazolo[1,5-a]-pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate. 29.-35. (canceled)
 36. The chemical entity of claim 1,wherein Z is

wherein X⁴ is —O—, —N(R^(*2))—, —S— or —C(O)—; each of n1 and n2 isindependently 0, 1 or 2, provided that n1+n2=0, 1 or 2; and eachinstance of R^(S7.4) is independently selected from (a) halo, (b1) C₁₋₂aliphatic, (b2) R^(#2-1), (c) —OR^(*2), (d) —N(R^(*2))₂ and (e)—SR^(†2).
 37. The chemical entity of claim 36, wherein each instance ofR^(S7.4) is independently selected from (a) —F, —Cl, —Br, (b1) C₁₋₂aliphatic, (b2) R^(#2-1), (c) —OR^(*2) and (d) —N(R^(*2))₂, wherein eachinstance of R^(#2-1) is independently C₁₋₂ alkyl unsubstituted orsubstituted with 1 substituent selected from (a) —F, —Cl, (c) —OR^(*2)and (d) —N(R^(*2))₂.
 38. The chemical entity of claim 36, whereinn1+n2=0 or
 1. 39. The chemical entity of claim 36, wherein the compoundis I-010(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate; I-019(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate; I-037(rac)-[(1R,2R,3S,4R)-4-{[2-(9H-carbazol-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate; I-056(rac)-((1R,2R,3S,4R)-4-((2-(Dibenzo[b,d]thiophen-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate; I-062(rac)-[(1R,2R,3S,4R)-4-{[2-(9H-carbazol-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2,3-dihydroxycyclopentyl]methylrel-sulfamate; I-085(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(9-oxo-9H-fluoren-2-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methylrel-sulfamate; I-093(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate; or I-103(rac)-((1R,2R,3S,4R)-4-(2-(dibenzo[b,d]furan-4-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-dihydroxycyclopentyl)methylrel-sulfamate. 40.-47. (canceled)
 48. A pharmaceutical compositioncomprising, the chemical entity of claim 1, and a pharmaceuticallyacceptable carrier. 49.-53. (canceled)
 54. A chemical entity comprisingthe compound((3aR,4R,6R,6aS)-2,2-dimethyl-6-((2-(3-((trifluoromethyl)thio)phenyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanolor a salt thereof.